The former MVP has a medial meniscus tear and there's no immediate timetable for his return.
Rose had an MRI in Los Angeles on Saturday after he was injured a night earlier at Portland. He won't be with the team for its remaining four games on its six-game trip.
The three-time All-Star sat out last season recovering from a torn anterior cruciate ligament in his left knee. Now, it's his other knee that's injured.
"It's sad, knowing how hard he worked to get back," said All-Star guard Chris Paul of the Clippers, who will host the Bulls on Sunday.
Rose's injury occurred in the third quarter against the Trail Blazers.
He lost his footing while trying to change direction to get back on defense when Nicolas Batum stole a pass from Joakim Noah and started the other way. Rose limped across the court and couldn't put any weight on his knee. After the Blazers scored, he came out of the game during a timeout.
It didn't appear there was any contact on the play. Rose was unable to return and was on crutches afterward.
"I feel bad for him," said Clippers All-Star Blake Griffin, who tore his meniscus in college at Oklahoma and was playing a few days later. "The good news is it's not nearly as bad as what he went through (before).
Even though the injury isn't as serious as a torn ACL, losing Rose for any chunk of time is obviously a huge blow for a team expecting to challenge LeBron James and the Miami Heat for supremacy in the Eastern Conference with its franchise player back.
"That helps that locker room because they know there's a return date," said Clippers coach Doc Rivers, who is close friends with Bulls coach Tom Thibodeau. "With ACLs, there's no return date."
The Bulls (6-5) were even eyeing a championship run for the first time since the Michael Jordan-Scottie Pippen era.
Now, there's a big cloud hanging over the franchise. And once again, it centers on Rose.
The latest injury rekindled memories of the 2012 playoff opener against Philadelphia, when he crumpled to the court near the end of the game with a torn ACL in his left knee. That sent the top-seeded Bulls toward a first-round exit and put them in a holding pattern last season while their star recuperated.
Many thought he would return at some point, particularly after he started practicing without restrictions. Instead, his recovery took on almost a circus-like feel.
Fans saw him shooting and dunking before games last season and wondered why he wasn't playing. Meanwhile, the Bulls fought injuries and illnesses on the way to 45 wins and a first-round playoff victory over Brooklyn before falling to Miami.
Along the way, his image took a hit.
Adidas released videos documenting his progress, but Rose mostly stayed in the background, saying little about his recovery. That changed midway through the season.
There was also speculation of a rift with the organization after older brother Reggie Rose ripped management for standing pat at the trade deadline, but Derrick Rose denied that.
All those issues faded into the background with Rose back this season. He had insisted he was returning better than ever, had no doubts he would regain his MVP form, but he was off to an up-and-down start after a dominant preseason.
A sore hamstring caused him to miss a game, and he is shooting just 35 percent. He was looking better the past two games, with 19 points in a loss at Denver and 20 against Portland.
AP Sports Writer Beth Harris in Los Angeles contributed to this report.