- 2372: The Enterprise launches, under the command of Captain Jean-Luc Picard. Originally named the USS Honorious, the ship was renamed after the Enterprise-D, which had been recently destroyed by the Duras Sisters.
- 2373: The Enterprise averts the second Borg invasion of Earth, killing the Borg Queen at the time, and helped Zefram Cochrane build the Phoenix, the first human spaceship with a warp drive.
- 2375: The Enterprise, along with the U.S.S. Cairo, helps repel the Breen attack on Earth during the Dominion War.
- 2379: The Enterprise lays the foundation of renewed and deepens diplomatic relations with the Romulan Star Empire when she defeats the Reman-based praetor Shinzon. The ship was severely damaged in the battle, which involved, among other things, a ramming attack.
- 2385: Captain Picard resigns his commission and becomes Ambassador to Vulcan. The Enterprise returns to Utopia Planitia for a refit.
- 2387: Due to a critical situation involving a massive rift to Fluidic Space, the Enterprise is relaunched under the command of Captain Data several months before her refit is complete. The Enterprise crew is credited with sealing the rift, which was the size of a small moon, and threatened an entire sector of the Klingon Empire's territory.
- 2397: Geordi La Forge is named captain of the U.S.S. Challenger, and Nog becomes chief engineer of the Enterprise.
- 2398: The Enterprise, along with the I.K.S. Gorkon, investigate the death of Ambassador K'mtok following an attack on the Klingon-Gorn negotiations.
- 2408: The Enterprise investigates the loss of contact with Starbase 236. During this mission, the Enterprise encounters Undine forces in Fluidic space. While the ship was destroyed, most of the crew, including Captain Data, survive, and are credited with turning the tide against the Undine.
- Jean-Luc Picard - Commanding Officer (2372-2385)
- Data - Chief Operations Officer (2372-2379); Commanding Officer (2387-2408)
- William T. Riker - Executive Officer (2372-2379)
- Deanna Troi - Counselor (2372-2379)
- Geordi La Forge - Chief Engineer (2372-2385; 2387-2397)
- Nog - Chief Engineer (2397-2408)
- Beverly Crusher - Chief Medical Officer (2372-2379; 2379-2385)
- Worf - Acting tactical officer (2373, 2375, 2379)
- “The Measure of Morality (Part 2)”: The Enterprise-E (or a simulacrum of it), along with several other starships Enterprise, the U.S.S. Defiant, U.S.S. Voyager, and the U.S.S. Discovery, assists the player's ship in a battle against a renegade Excalbian simulacrum Borg Queen.
- “Vorgon Conclusions”: The Player pursues Vorgon agents to 24th century Earth during the Breen attack on Starfleet Command; during the mission, the player views news broadcasts which mention the Enterprise-E and the U.S.S. Cairo leading a counterattack against the Breen invasion force.
- “Message From Another Time III”: The player watches an after-action report recorded by Commander Nereda wherein she recounts foiling a plan by Na'kuhl agents to reprogram the android B-4 to sabotage the Enterprise-E's warp core to explode while the ship was in orbit of Romulus.
- “One Night in Bozeman”: The mission takes place while the Enterprise-E is in the orbit of Earth in 2063. It and her crew are referenced, heard and occasionally killed throughout the mission.
- A plaque depicting the Enterprise-E can be seen inside starbases whose fleets have completed the special project "History and Movement".
- Prior to the Sovereign-class getting a screen-accurate revamp in 2016, players could mimic the appearance of the Enterprise-E on Sovereign-class Assault Cruisers by choosing the Andromeda color pattern in the ship customization editor.
- In the mission "The Measure of Morality (Part 2)", the Enterprise-E is shown to use Ability: Riker Maneuver, which was inspired by the improvised tactic used by then-Commander William T. Riker while in command of the Enterprise-E during the events of Star Trek: Insurrection.
- USS Enterprise (NCC-1701-E) at Memory Alpha, the Star Trek Wiki.
- USS Enterprise (NCC-1701-E) at Memory Beta, the non-canon Star Trek Wiki.
NCC-1701-D • NCC-1701-E • NCC-1701-F (Mirror) • NCC-1701-J