Enterprise sailed south on a shakedown cruise which took her to Rio de Janeiro, Brazil. After her return she operated along the east coast and in the Caribbean until April of 1939 when she was ordered to duty in the Pacific. Based first out of San Diego and then in Pearl Harbor, the carrier trained herself and her aircraft squadrons for any eventuality, and carried aircraft among the island bases of the Pacific. Enterprise had just completed one such mission, delivering Marine Corps Fighter Squadron 211 to Wake Island on 2 December 1941, and was en route to Hawaii when the Japanese attacked Pearl Harbor.

Enterprise's scout planes arrived over Pearl Harbor during the attack and, though surprised, immediately went into action in defense of the naval base. The carrier, meanwhile, launched her remaining aircraft in a fruitless search for the Japanese striking force. Enterprise put into Pearl Harbor for fuel and supplies on December and sailed early the next morning to patrol against possible additional attacks on the Hawaiian Islands. While the group did not encounter any surface ships, Enterprise aircraft scored a kill by sinking the Japanese submarine 1-170 in 23º 45' N., 155º 35' W., on 10 December 1941.

During the last two weeks of December 1941, Enterprise and her group steamed to the westward of Hawaii to cover those islands while two other carrier groups made a belated attempt to relieve Wake Island. After a brief rest at Pearl Harbor, the Enterprise group sailed on 11 January 1942 to protect convoys reinforcing Samoa. On 1 February the task force dealt a hard blow to Kwajalein, Wotje, and Maloelap in the Marshall Islands, sinking three ships, damaging eight, and destroying numerous airplanes and ground facilities. Enterprise received only minor damage in the Japanese counterattack, as her force retired to Pearl Harbor.

During the next month Enterprise's force swept the central Pacific, blasting enemy installations on Wake and Marcus Islands, then received minor alterations and repairs at Pearl Harbor. On 8 April 1942 she departed to rendezvous with USS Hornet (CV 8) and sail westward to launch 16 Army B-25 bombers in a raid on Tokyo. While Enterprise fighters flew combat air patrol, the B-25s roared into the air on 18 April and raced undetected the 600 miles to their target. The task force, its presence known to the enemy, reversed course and returned to Pearl Harbor on 25 April.

Five days later, the "Big E" was speeding toward the South Pacific to reinforce the U.S. carriers operating in the Coral Sea. Distance proved too great to conquer in time, and the Battle of the Coral Sea was history before Enterprise could reach her destination. Ordered back to Hawaii, the carrier entered Pearl Harbor on 26 May and began intensive preparations to meet the expected Japanese thrust at Midway Island. Two days later she sortied as flagship of Rear Admiral Raymond A. Spruance, Commander Task Force 16 (CTF 16), with orders "to hold Midway and inflict maximum damage on the enemy by strong attrition tactics." With Enterprise in TF 16 were Hornet, 6 cruisers, and 10 destroyers. On 30 May, TF 17, Rear Admiral Frank J. Fletcher in USS Yorktown (CV 5), with two cruisers, and six destroyers, sailed to support TF 16; as senior officer, Rear Admiral Fletcher became "Officer in Tactical Command."

The battle was joined on the morning of 4 June 1942 when four Japanese carriers, unaware of the presence of U.S. forces, launched attacks on Midway Island. Just 3 hours after the first bomb fell on Midway, planes from Hornet struck the enemy force, and 30 minutes later Enterprise and Yorktown aircraft streaked in to join in smashing the Japanese carriers. Each side hurled attacks at the other during the day in one of history's most decisive battles. Though the forces were in contact to 7 June, by the end of the 4th the outcome had been decided and the tide of the war in the Pacific had been turned in the United States' favor. Yorktown and USS Hammann (DD-412) were the only United States ships sunk, but TFs 16 and 17 lost a total of 113 planes, 61 of them in combat, during the battle. Japanese losses, far more severe, consisted of 4 carriers, one cruiser, and 272 carrier aircraft. Enterprise and all other ships of TFs 16 and 17 came through undamaged, returning to Pearl Harbor on 13 June 1942.

After a month of rest and overhaul, Enterprise sailed on 15 July for the South Pacific where she joined TF 61 to support the amphibious landings in the Solomon Islands on 8 August. For the next 2 weeks, the carrier and her planes guarded seaborne communication lines southwest of the Solomons. On 24 August 1942, a strong Japanese force was sighted some 200 miles north of Guadalcanal and TF 61 sent planes to the attack. An enemy light carrier was sent to the bottom and the Japanese troops intended for Guadalcanal were forced back. Enterprise suffered most heavily of the United States ships, 3 direct hits and 4 near misses killed 74, wounded 9S, and inflicted serious damage on the carrier. But well-trained damage control parties, and quick hard work patched her up so that she was able to return to Hawaii under her own power.

Repaired at Pearl Harbor from 10 September to 16 October 1942, Enterprise departed once more for the South Pacific where with Hornet, she formed TF 61. On 26 October, Enterprise scout planes located a Japanese carrier force and the Battle of the Santa Cruz Island was underway. Enterprise aircraft struck carriers, battleships, and cruisers during the struggle, while the "Big E" herself underwent intensive attack. Hit twice by bombs, Enterprise lost 44 killed and had 75 wounded. Despite serious damage, she continued in action and took on board a large number of planes from Hornet when that carrier had to be abandoned. Though the American losses of a carrier and a destroyer were more severe than the Japanese loss of one light cruiser, the battle gained priceless time to reinforce Guadalcanal against the next enemy onslaught.

Enterprise entered Noumea, New Caledonia, on 30 October 1942 for repairs, but a new Japanese thrust at the Solomons demanded her presence and she sailed on 11 November, repair crews from USS Vestal (AR-4) still on board, working vigorously. Two days later, "Big E" planes swarmed down on an enemy force and disabled a battleship which was sunk later by other American aircraft, and on 14 November, aviators from Enterprise helped to despatch a heavy cruiser. When the Naval Battle of Guadalcanal ended on 15 November 1942, Enterprise had shared in sinking 16 ships and damaging 8 more. The carrier returned to Noumea on 16 November to complete her repairs.

Sailing again on 4 December, Enterprise trained out of Espiritu Santo, New Hebrides, until 28 January 1943 when she departed for the Solomons area. On 30 January her fighters flew combat air patrol for a cruiser- destroyer group during the Battle of Rennell Island. Despite the destruction of a large majority of the attacking Japanese bombers by Enterprise planes, USS Chicago (CA-29) was sunk by aerial torpedoes. Detached after the battle, the carrier arrived at Espiritu Santo on 1 February, and for the next 3 months operated out of that base, covering U.S. surface forces up to the Solomons. Enterprise then steamed to Pearl Harbor where on 27 May 1943, Admiral Chester W. Nimitz presented the ship with the first Presidential Unit Citation won by an aircraft carrier. On 20 July 1943 she entered Puget Sound Navy Yard, Bremerton, Wash., for a much needed overhaul.

Back in action waters by mid-November, Enterprise joined in providing close air support to the Marines landing on Makin Island, from 19 to 21 November. On the night of 26 November 1943, the "Big E" introduced carrier-based night fighter operations in the Pacific when a three-plane team from the ship broke up a large group of land-based bombers attacking TG 50.2. After heavy strike by aircraft of TF 50 against Kwajalein on 4 December, Enterprise returned to Pearl Harbor six days later. The carrier's next operation was with TF 58 in softening up the Marshall Islands and supporting the landings on Kwajalein, from 29 January to 3 February 1944. Then Enterprise sailed, still with TF 58, to strike the Japanese naval base at Truk in the Caroline Islands, on 7 February. Again the "Big E" made aviation history when she launched the first night radar bombing attack from any U.S. carrier. The 12 torpedo bombers in this strike achieved excellent results, accounting for nearly one-third of the 200,000 tons of shipping destroyed by the aircraft of the task force.

Detached from TF 58, Enterprise launched raids on Jaluit Atoll on 20 February, then steamed to Majuro and Espiritu Santo. Sailing 15 March 1944 in TG 36.1, she provided air cover and close support for the landings on Emirau Island (19-25 March). The carrier rejoined CF 58 on 26 March and for the next 12 days joined in the series of hard-hitting strikes against the Yap, Ulithi, Woleai, and the Palau Islands. After a week's rest and replenishment at Majuro, Enterprise sailed 14 April to support landings in the Hollandia area of few Guinea, and then hit Truk again (29-30 April).

On 6 June 1944, the "Big E" and her companions of TG 58.3 sortied from Majuro to strike with the rest of TF 58, the Mariana Islands. Blasting Saipan, Rota, and Guam between 11 and 14 June, Enterprise pilots gave direct support to the landings on Saipan on 15 June, and covered the troops ashore for the next two days. Aware of a major Japanese attempt to break up the invasion of Saipan, Admiral Raymond A. Spruance, Commander 6th Fleet, positioned TF 58 to meet the thrust. On 19 June 1944 took place the greatest carrier aircraft battle in history. For over eight hours airmen of the United States and Imperial Japanese navies fought in the skies over TF 58 and the Marianas. By the end of the day, a United States victory was apparent, and at the conclusion of the strikes against the Japanese fleet on 20 June, the triumph became complete. Six American ships had been damaged, and 130 planes and a total of 76 pilots and aircrewmen had been lost. But with a major assist from U.S. submarines, 3 Japanese carriers were sunk, and 426 ship-based aircraft were destroyed. Japanese naval aviation never recovered from this blow.

The Battle of the Philippine Sea over, Enterprise and her companions continued to support the Saipan campaign through 5 July 1944. Enterprise then sailed for Pearl Harbor and a month of rest and overhaul. Back in action waters on 24 August, the carrier sailed with TF 38 in that force's aerial assault on the Volcano and Bonin Islands from 31 August to 2 September, and Yap, Ulithi, and the Palaus from 6 to 8 September. After operating west of the Palau Islands, the "Big E" joined other units of TF 38 on 7 October, and shaped course to the northward. From 10 to 20 October her aviators roared over Okinawa, Formosa, and the Philippines, blasting enemy airfields, shore installations, and shipping in preparation for the assault on Leyte. After supporting the Leyte landings on 20 October, Enterprise headed for Ulithi to replenish but the approach of the Japanese fleet on 23 October, brought her racing back into action. In the Battle for Leyte Gulf (23-26 October), Enterprise planes struck all three groups of enemy forces, battering battleships and destroyers before the action ended. The carrier remained on patrol east of Samar and Leyte until the end of October, then retired to Ulithi for supplies. During November, her aircraft struck targets in the Manila area, and the island of Yap. The "Big E" returned to Pearl Harbor on 6 December 1944.

Sailing 24 December for the Philippine area, Enterprise carried on board an air group specially trained in night carrier operations. She joined TG 38.5 and swept the waters north of Luzon and of the China Sea during January of 1945, striking shore targets and shipping from Formosa to Indochina. After a brief visit to Ulithi, the "Big E" joined TG 58.5 on 10 February 1945 and provided day and night combat air patrol for TF 58 as it struck Tokyo on 16 and 17 February. She then supported the Marines on Iwo Jima from the day of the landings, 19 February 1945, until 9 March when she sailed for Ulithi. During one part of that period, Enterprise kept aircraft aloft continuously over Iwo Jima for 174 hours. Departing Ulithi 15 March, the carrier continued her night work in raids against Kyushu, Honshu, and shipping in the Inland Sea of Japan. Damaged slightly by an enemy bomb on 18 March, Enterprise entered Ulithi six days later for repairs. Back in action on 5 April, she supported the Okinawa operation until again damaged (11 April), this time by a suicide plane, and forced back to Ulithi. Off Okinawa once more on 6 May 1945, Enterprise flew patrols around the clock as the menace of the kamikaze increased. On 14 May 1945, the "Big E" suffered her last wound of World War II when a suicide plane destroyed her forward elevator, killing 14 and wounding 34 men. The carrier sailed for repairs at the Puget Sound Navy Yard, arriving 7 June 1945.

Restored to peak condition, Enterprise voyaged to Pearl Harbor, returning to the States with some 1,100 servicemen due for discharge, then sailed on to New York, arriving 17 October 1945. Two weeks later she proceeded to Boston for installation of additional berthing facilities, then began a series of "Magic Carpet" voyages to Europe, bringing more than 10,000 veterans home in her final service to her country.

Enterprise entered the New York Naval Shipyard on 18 January 1946 for inactivation, and was decommissioned on 17 February 1947. The "Big E" was sold on 1 July 1958.