Launched in 2372 after the loss of her predecessor, the Sovereign-class U.S.S. Enterprise NCC-1701-E was captained once again by Jean-Luc Picard alongside most of the original senior staff of the Enterprise-D. A year later, the Enterprise-E was near completion of its shakedown cruise when the second Borg incursion against Federation space occurred. 

Picard defied orders and took his ship and crew into combat for the first time. The arrival of the Enterprise in Sector 001 proved decisive, with Picard assuming command of the fleet and directing fire on the gigantic Borg Cube, leading to its destruction. An attempt to alter history by the Borg Queen and drones that had beamed aboard was also thwarted, though the Enterprise came close to being lost when the cybernetic beings began assimilating the ship.

With the onset of the Dominion War in 2373, the Enterprise was kept away from the front lines, with the ship instead dispatched on a flurry of diplomatic missions to bolster Federation support. When the war ended, the Federation and Romulan Empire emerged as the two strongest superpowers, and an apparent thawing in diplomatic relations ensued. 

The Enterprise-E became the first Federation starship to visit Romulus, but it quickly emerged the peace overtures were a ruse. Shinzon, the new Romulan praetor, was in fact a clone of Picard himself and he had decided to wage war on the Federation. The Enterprise intercepted and fought Shinzon to a standstill, with his final defeat only occurring thanks to the sacrifice of Lieutenant Commander Data. 

The Enterprise returned to Earth for repairs and her long-standing command crew broke up to go to new postings, with Commander Riker promoted to the Captain of the U.S.S. Titan NCC-80102. Picard was later promoted to Admiral and left the Enterprise in 2381 to lead the evacuation of Romulus from an impending supernova.