Holmes caught a pass for 4 yards in the right flat and turned to make a football move. He planted his left foot and immediately dropped to the MetLife Stadium turf.
Holmes immediately let go of the ball when he fell to the turf. He wasn't touched. San Francisco 49ers cornerback Carlos Rodgers scooped up the fumble and returned it 51 yards for a touchdown and a 24-0 lead.
Holmes barely put any weight on the leg while being helped off the field and went straight to the cart.
"That's really too bad," Jets quarterback Mark Sanchez said. "You'd love him to hang on to the ball, but at the same time, the guy's going down and he hurt himself, kind of assumed the play was over. Just another tough play."
"We've got to play with what we've got, and it's going to be on me to be much more accurate than today and last week and play well with the receivers we have."
Holmes is the No. 1 receiver on the Jets' roster and entered the day with 16 catches for 243 yards and one touchdown this season.
UPDATE: ESPN New York cited a source in reporting that Holmes will have an MRI on Monday morning. X-rays taken Sunday at MetLife Stadium were negative.
Follow Kareem Copeland on Twitter @kareemcopeland.