Jones - who had been playing with a hairline fibula fracture in his left leg in recent weeks - collapsed to the turf clutching his right leg in a non-contact incident in the first quarter of Sunday's game.
The 28-year-old slammed his helmet to the ground in frustration following the incident before being helped off the field. He later reappeared on the sidelines wearing a protective boot on his right leg.
Colts head coach Shane Steichen said Jones injury "could be season-ending."
"Not for sure, but it's not looking good," Steichen said.
Jones has been instrumental in leading a resurgent Colts team this season, putting the franchise firmly on course to reach the playoffs for the first time since the 2020 campaign.
The Colts' loss on Sunday saw them drop to second in the AFC South at 8-5, with Jacksonville vaulting over them into first place at 9-4.