Specifics of the deal were not announced, though Strikeforce termed it a "multi-year" contract.
Melendez has not fought since April 2010, after routing DREAM champion Shinya Aoki in a five-round unanimous decision. Afterward, he decided to take the rest of the year off to spend time with his family.
Melendez (18-2) is considered one of the top lightweights in the world, and is the winner of four straight fights.
He first captured the Strikeforce championship in June 2006 with a decision win over Clay Guida. He eventually lost the belt to Josh Thomson, but regained it in his very next fight, and eventually avenged the loss to Thomson as well.
The 28-year-old is part of the Cesar Gracie team. Now, Strikeforce will be tasked with finding him an opponent as Melendez looks to get back into action soon.
"I'm healthy again and excited about fighting again real soon,'' Melendez said in the press release. "It doesn't matter who I fight. I just want to get back in there and rip.''