Lillard, a six-time All-Star, came up limping with just over five minutes to go in the third quarter and headed straight for the locker room. He did not return.
Speaking after the game, Lillard said the calf felt a little tight before tipoff and that the tightness didn't go away in the first half, leading him to put some compression on it at halftime. He said when he rose up for a shot in the third quarter, it tightened up more, leading to his exit.
"It wasn't nothing that I was overly concerned with," he told reporters. "I just know that it wouldn't make sense to try and push through it in the fifth game of the season."
Lillard said he didn't have an MRI or any additional tests.
"Honestly, if this was a playoff game, I would have played," he said. "It would have been tight and uncomfortable, but I would have played. If that gives you any indication of how concerned I am now or would have been."
"Now I've just got to be smart, and make sure I'm getting a couple of treatment sessions in each day, and just try to stretch it," he said. "So probably not going to be playing that game on Friday. That will give me six days of maybe two sessions some days, three sessions other days, and try to be ready for that one. We'll see."
Lillard had 22 points, including four 3-pointers, before he was injured. He scored 30-plus points in three of the Blazers' first four games this season.
The injury, however slight, was scary for the Blazers because Lillard missed 47 games last season with a nagging abdominal injury that required surgery. In the first four games of this season, he finally looked fit and agile.
"It's early. We've gotten off to a good start. Things feel good. I haven't felt this good since my second or third year," he said. "Everything that I did this summer is just adding up. I feel fast, I feel strong. I don't get tired. And I don't want to lose that. So I've got to be patient and I can't get ahead of myself."
Portland was the last undefeated team in the Western Conference.
The Associated Press contributed to this report.