With just under seven minutes to play in a blowout 108-90 Houston Rockets win, Randle fell hard after a drive to the lane, breaking his tibia, the Lakers announced.
The Lakers, who lost Kobe Bryant to injury for all but six games of last season, had already been hit with injuries even before Randle got hurt.
Future hall of famer Steve Nash is expected to miss the entire season, possibly ending his career with a back injury.
Randle, the number seven overall pick in the NBA entry draft, was stretchered off the court after being treated by doctors, who put his leg in an air cast.
The six-foot-nine, 250-pound Randle was one-for-three from the floor for two points in 13 minutes of playing time.