Los Angeles lost its sixth game in a row and fell to 8-13 at home.
It was the fourth time in Jefferson's 10-year career that he had produced 40 points and continued a hot streak in which he had 32 and 35 points in his previous two games.
He hit 18-of-32 shots from the field while playing 39 minutes, helping the Bobcats build a 12-point lead heading into the fourth quarter. The Lakers came no closer than eight during the final period and that was in the final minute.
Charlotte won for the fourth time in five games and will try for its first three-game winning streak of the season on Saturday at Phoenix.