The USS Enterprise (NCC-1701-E) was a 24th century Federation Sovereign-class starship operated by Starfleet. This ship was the sixth Federation starship to bear the name Enterprise. On stardate 49827.5, the Sovereign-class Enterprise-E, seen as the pinnacle of Starfleet ship design, was launched from San Francisco Fleet Yards, with Captain Jean-Luc Picard in command once more. Much of the crew of the Enterprise-D had been reassigned there, including almost the entire senior staff. The sole exception was Lieutenant Commander Worf, who had already transferred to the space station Deep Space 9. After almost a year in space, the Enterprise was ordered to the Romulan Neutral Zone during the second Borg incursion. Starfleet was officially concerned about possible Romulan military action since many of the available ships had been diverted to fight the Borg, but in reality, Starfleet was concerned about Picard's presence at the battle. However, shortly after the Federation fleet engaged the Borg cube, Picard disobeyed orders and returned to Earth to assist the fleet. Once there, Picard became aware of a battle-induced weakness in the Borg ship due to his residual link to the Collective, and ordered all the ships in the fleet to concentrate their fire on that section of the ship. As a result, the Borg vessel was destroyed and the Battle of Sector 001 was a victory for Starfleet. Before the Borg cube was destroyed, it launched a second vessel towards Earth. This ship created a temporal vortex and traveled back to the year 2063 in order to stop Zefram Cochrane from launching his historic warp ship, the Phoenix. Their hope was to prevent first contact with the Vulcans, and assimilate Earth before the Federation could be formed to resist them. The Enterprise, protected from the alterations in the timeline by the vortex, chased the Borg into the past and destroyed their ship, then sent an away team to help Cochrane repair the Phoenix. 

However, the ship's sensors and shields were damaged during the trip through the vortex, and unbeknownst to the crew, several Borg drones transported aboard the Enterprise before their ship exploded. They began to assimilatethe ship's engineering section below Deck 10. They also attempted to build an interplexing beacon on the Enterprise deflector dish to contact the Borg Collective of that time period. 

A three-man team led by Captain Picard stopped the beacon from being completed by separating the deflector from the ship by disengaging the magnetic locks and then destroying it. However, the Borg's ability to adapt to the handheld weapons of the Enterprise crew made stopping them impossible, and Picard realized that the fight was a lost cause. After great consideration, he reluctantly ordered the evacuation of the ship, and activated the ship's auto-destruct sequence to prevent the Borg from interfering with the Phoenix flight. 

He eventually confronted a Borg Queen in main engineering, only to find, to his horror, that the Borg had apparently turned Lieutenant Commander Data to their side. He aborted the auto-destruct and fired three quantum torpedoes at the Phoenix, ostensibly intending to destroy it. However, the torpedoes completely missed their target, and Data revealed that he had in fact simply been deceiving the Borg. After mockingly repeating the Borg mantra, Data smashed open a plasma coolant tank, flooding engineering with plasma coolant and liquifying the Borg Queen and all the drones in engineering. This apparently disabled all the other drones on the ship, and allowed Data and Picard to recapture the vessel.

The Enterprise crew was successful in helping Cochrane make his flight and instigate First Contact with Vulcans. The ship then returned to 2373 where she was repaired and returned to service. 

With the Federation Diplomatic Corps attempting to negotiate an end to the Dominion War, the Enterprise was relegated to a diplomatic role, much to the dissatisfaction of Captain Picard. In 2375, the Enterprise was conducting a diplomatic mission with the Evora, a new Federation protectorate species, and was scheduled to resolve a dispute in the Goren system when her crew became embroiled in a plot by the Son'a, assisted by Starfleet Admiral Matthew Dougherty, to forcibly remove the Ba'ku from their isolated homeworld in the Briar Patch. 

The Son'a turned out to be vengeful former Ba'ku who had been exiled from the planet after a failed coup a century prior. They planned to harvest metaphasic radiation from the planet's ring system, and needed Starfleet's cooperation to carry out the plan. Captain Picard felt the relocation of the Ba'ku was a severe violation of the Prime Directive and resigned his commission, leading a team of Enterprise crewmembers to the Ba'ku planet to prevent their capture and removal. 

Commander William T. Riker was instructed to take the Enterprise and contact the Federation Council to alert them of Admiral Dougherty's treachery. However, the Enterprise was required to navigate an area of space known as the Briar Patch in order to contact Starfleet Command. This area disrupted communications as well as the ship's impulse drive. 

Two Son'a battle cruisers were sent by Ahdar Ru'afo to intercept the Enterprise before she left the Briar Patch, and severely damaged the ship in the process. The warp core was ejected in order to seal a dangerous tear in subspace created by the isolytic weaponry of the Son'a. 

Riker was able to outwit the Son'a by collecting metreon gas native to the Briar Patch then venting it behind the ship. When the Son'a used their weapons, the gas exploded, destroying one ship and severely damaging the other. Geordi La Forge half-jokingly commented that the tactic could become known as the Riker Maneuver.

The Enterprise visited Earth for several days in 2376, around the time the Pathfinder Project made contact with the USS Voyager, and conducted a mission about seven light years from Earth the following year. According to Deanna Troi, it was an important mission, but the objective was never discussed.

Sometime between 2375 and 2379 the Enterprise underwent a major refit. Four additional aft-facing photon torpedo tubes were added, along with one more forward-facing tube: a twin launcher aft of the bridge, a single launcher above the aft hangar deck, and a single launcher at the forward base of the bridge terracing. The bridge was refitted with handrails and the consoles were improved across the port and starboard walls with more detailed displays. Additionally, new nacelle pylons were fitted at that time, slightly longer, broader and more sharply swept than the originals, and fitted with four additional phaser arrays.

In 2379, the Enterprise returned to Earth for the wedding of William T. Riker and Deanna Troi. She departed for Betazed, where another ceremony, a traditional Betazoid wedding, was scheduled.

While en route, the ship detected unusual positronic signals from the Kolarin system, discovering another Soong-type android, the prototype B-4. Shortly following, the Enterprise was ordered to Romulus for a meeting with the new Praetor, Shinzon, who apparently wanted to initiate peace talks. Both the discovery of B-4 and the peace overtures turned out to be a ruse to capture Captain Picard and discover tactical positions of Starfleet vessels.

Once it became clear Shinzon was going to use his starship, the Scimitar, to destroy all life on Earth and wage war on the Federation, the Enterprise was to join Star Fleet Battle Group Omega and make a stand against Shinzon. Shinzon caught up to the Enterprise in the Bassen Rift, and in the ensuing confrontation, the vessel was severely damaged, including a major hull breach on the bridge, destroying the viewscreen and controls and disabling the warp core.

As a last resort, Picard ordered Counselor Deanna Troi to take control of the Enterprise and have it ram the Scimitar, causing the destruction of much of the saucer section's forward area. The collision disabled the Scimitar, but Shinzon, driven by vengeance, activated his deadly thalaron weapon and trained it on the Enterprise.

The weapon was overloaded and the Scimitar was destroyed due to interference from Commander Data, who sacrificed himself to save the Enterprise, Picard, and, indirectly, Earth.

Following the Scimitar incident, the Enterprise returned to Earth where it underwent an extensive repair in one of the orbiting spacedocks.