The Cavaliers, who led by 10 at the half, had won 23 consecutive home games before the loss.
With Kobe Bryant struggling with the flu, forward Lamar Odom took over the Lakers' scoring load with season highs of 28 points and 17 rebounds. Bryant finished with 19 points, including a key field goal in the fourth quarter.
LeBron James had 16 points and 12 assists for Cleveland in a disappointing performance in which he made only five of 20 shots from the floor.
Zydrunas Ilgauskas led the Cavaliers with 22 points while Mo Williams pitched in with 19.
The win completed a 6-0 road trip for the Lakers, who on Thursday ended Eastern Conference leader Boston's 12-game winning streak.
