The 41-year-old Hopkins, who claimed he would retire after the bout, won by a 118-109 count on all three score-cards after jumping two weight classes.
He was a long-time light middle-weight champion.
Tarver, 37, who reportedly had to lose 40 pounds to make the weight for the bout, also lost a $250,000 bet with Hopkins that he would stop Hopkins within five rounds.
Hopkins' record rose to 47-4-1 with 32 knockouts. Tarver fell to 24-4 with 18 knockouts.
"I told people they were going to be surprised by this fight," Hopkins told the Philadelphia Inquirer. "I told them it was going to be easy for me. I was in good shape and I know I'm good with southpaws."
He never lost to a left-handed boxer in 10 bouts.