Holden ruled out for another six months
Holden only returned to first-team action last week after half-a-year out with the knee injury, which was suffered against Manchester United in March.
"Floored, devastated, gutted, just a few words I can think of. I will continue to fight and I'm ready for another tough journey," Holden said on Twitter.
Bolton said on their website that the damage to Holden's knee was discovered during a "routine procedural" on the player.
"He went in for the procedure this afternoon and it was picked up that the cartilage was damaged and needed to be repaired, which has now happened, and we will now support Stuart as he begins his recovery," said Bolton manager Owen Coyle.
"It is a big, big blow for Stuart because he has worked so hard after he sustained the injury, but obviously the most important aspect is to ensure Stuart's well being and that's what we are focused on."
Holden's new absence is a setback for Bolton, who are bottom of the Premier League having lost five of their opening six games.
The midfielder's injury is also a blow for United States head coach Jurgen Klinsmann as he prepares for next year's World Cup qualifiers.
The German coach recently visited Bolton to check up on Holden's progress and was hoping to see the Scotland-born player back in his squad.