The second starship Potemkin was constructed over a period of three years and commissioned in 2305. It served with valor and distinction for twenty years before its first major refit. In 2330, it encountered a subspace distortion and disappeared. Discovered adrift along the edge of the Betreka Nebula in 2341 by a survey ship, it was towed to Starbase G-6 and recommissioned a year later. It served for another fifteen years and was refitted for a third time in 2356.

In 2361, William T. Riker was assigned to the Potemkin as a lieutenant. He later would lead an away team to Nervala IV and would be duplicated by a transporter malfunction caused by an energy distortion field surrounding the planet. Aboard the Potemkin, Riker first tried the unconventional tactic of positioning the ship over a planet's magnetic pole to confuse another ship's sensors. Also during 2361, the Potemkin became the last starship to visit the failed colony at Turkana IV (prior to the U.S.S. Enterprise-D's visit in 2367).

The Potemkin underwent a fourth refit in 2368.