The American dropped Calzaghe with a straight right in the opening round, and once again used his defensive skills to wrong-foot his talented opponent.
However as the fight progressed Calzaghe found his rhythm and was able to step in and land effective punches.
"He caught me in the first round," Calzaghe said.
"He caught me with a flash knockdown. It was only the third time I've been on the floor."
The Welshman admitted he found it difficult to solve Hopkins in the early rounds.
|"I knew it wasn't going to be pretty, but a win is a win."|
"I had to be patient," Calzaghe said.
"It's very difficult to pin Bernard down. He's very wiley. I knew it wasn't going to be pretty, but a win is a win."
Calzaghe's aggressive pursuit of Hopkins and his clean punches earned him the decision from two judges, with Chuck Giampa scoring it 116-111 and Ted Gimza making it 115-112 for the Welshman, while Adalaide Byrd marked it 114-113 for Hopkins.
Hopkins was defiant in defeat, implying the decision should have gone to him.
"Look at my face, I don't have a bruise. I busted him up," the American said.
"I took a guy to school who was undefeated."
The aging warrior denied that he slowed down in the middle rounds, with his few punches losing their sting.
"I was just pacing myself for the long haul," he said.
Hopkins said he would talk to his partners at Oscar de la Hoya's Golden Boy promotions and his wife before making any decision about his future in the ring.
Calzaghe, who is the longest-reigning world champion in boxing and has defended his various titles 21 times, said he didn't yet know who he would seek to take on next.
Kelly Pavlik, the unbeaten WBC middleweight champion who will defend his crown on June 7 against Welshman Gary Lockett at Atlantic City, New Jersey, has been mentioned, as has the man Pavlik took his title from - Jermain Taylor - and another US legend, Roy Jones.
"I'm not sure," Calzaghe said.
"I'm a legend killer - maybe Roy Jones."