Lee has practiced just a few times since injuring his right hamstring on Aug. 5, during the first week of training camp.
Coach Gus Bradley said "we're getting our heads together and trying to figure out a way and what's best for him."
"I don't know how long it's going to be, but I think we really need to take a look at it and see what would be the benefit of some time," Bradley said Friday. "I think that's what we're looking at right now. That time could be a couple of days to a week."
A second-round draft pick from USC in 2014, Lee has missed significant chunks of time with ankle, hamstring and knee injuries. He sat out three games last season after injuring his right hamstring in practice and then spent another six weeks getting back to full speed.
He finished his rookie year with 37 catches for 422 yards and a touchdown.
But Lee was back on the sideline with a knee injury when the team began organized team activities in May. He was healthy for the start of camp, but was on the field just three days before ending up in the training room again.
Lee missed the opener last month because of the nagging hamstring and tweaked it again in last week's loss at New England.
"It's frustrating," Lee said Friday. "You always want to be out there doing your job. ... But at the end of the day, your health is very important. You want to get right before you actually come back and do the things you need to do. It's frustrating, yeah, but I think about it as far as this: I don't want to come in every day with a negative mindset. I don't think that'll help me heal faster. I think that'll make it even worse.
"I think about just coming in with a positive mindset and thinking about the positive. I'm not out for the season. Yeah, I want to be out there playing, but I'm not out for the season. I've got time so we're just doing the right things right now."
Starting right guard Brandon Linder also won't play against the Colts. Linder tried to play through a shoulder injury last week but clearly needed time off to heal. Rookie A.J. Cann is expected to make his first start in Linder's place.
The Jaguars also ruled out defensive tackle Sen'Derrick Marks (knee), tight end Julius Thomas (hand) and running back Denard Robinson (knee). Safety Sergio Brown (calf) was listed as doubtful.
Left tackle Luke Joeckel, safety Johnathan Cyprien and defensive end Andre Branch will return after missing games.