James checked out for the final time with 6:42 remaining in the fourth quarter and the Lakers down 16 points.
He said postgame that his ankle has continued to bother him since returning Friday.
"The last two games at halftime, it has gotten a little sore on me, a little tight," he said, courtesy of Ryan Ward of Lakers Nation.
He added: "I don't have too much level of concern, but I need to be healthy."
Lakers head coach Frank Vogel said the team made the decision not to let James re-enter the contest.
"He was battling some soreness," Vogel said, according to ESPN's Dave McMenamin. "We decided not to bring him back. We'll see how he's feeling tomorrow."
The 36-year-old sprained the same ankle earlier in the year and missed 20 consecutive games as a result before returning Friday against the Sacramento Kings. He was initially listed as questionable for Sunday's contest because of the ailment.
That sideline spell was the longest injury absence of James' career, surpassing the 17 games he missed in 2018-19 due to a groin strain.
After tallying 16 points, eight rebounds, and seven assists in nearly 32 minutes in his return Friday, James said he doesn't believe he'll ever be a fully healthy player again.
"I knew I wasn't going to get back to 100%. It's impossible," he said, per McMenamin. "I don't think I will ever get back to 100% in my career."