The former ER and Glee actor will appear in a season-long arc for the USA Network's upcoming third season, reports Deadline.
He will portray a character named Connor McClane, the founder of global sports and entertainment management company V3.
McClane is said to be ruthless in his quest to sign Dr Dani (Callie Thorne) for his company after her success with TK (Mehcad Brooks) and the New York Hawks.
John Stamos recently signed up for the lead role in NBC drama pilot I Am Victor.
Should the show be picked up for a full season, he will return to filming following his stint on Necessary Roughness.
Necessary Roughness is centred around tough divorcee Danielle 'Dani' Santino, who works as a therapist for a number of celebrities including athletes, musicians and politicians.
Stamos is best known for his TV roles including Jesse Katsopolis in Full House and Dr Tony Gates in ER.