Los Angeles trailed by one entering the fourth quarter, but scored seven in a row beginning at the 3-minute mark to pull away from the Pacers.
Bryant suffered a severely sprained ankle on Thursday in the final seconds of a loss to Atlanta and was declared by the Lakers to be out indefinitely.
He started Friday's game with the ankle heavily taped and played the entire first quarter without scoring a point. He left the game after the opening period, however, and did not return.
Howard scored 20 points and grabbed 12 rebounds while Metta World Peace chipped in 19 points for the Lakers. Los Angeles won for the fifth time in six games.
George Hill went 11-of-19 from the field and scored 27 points for the Pacers.
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