Bryant, who also finished with the highest-scoring game in the NBA this season, left to a loud ovation after the 24th 50-point game of his career. It was also his fifth 40-point game here.
Pau Gasol added 31 points and 14 rebounds in the Lakers' first game since losing Bynum, their starting center, for eight to 12 weeks with a torn medial collateral ligament in his right knee.
They'll be fine without him if Bryant plays the way he did Monday, going 19-of-31 with an array of tough jumpers, powerful drives to the basket and perfect foul shooting. He also hit all 20 free throws.
Bynum was hurt Saturday at Memphis when Bryant missed a driving shot, then crashed into his leg. The center isn't expected to need surgery and said he was confident he would return in time for the playoffs.
Lamar Odom moved into the starting lineup and Gasol slid to the center spot to replace Bynum, who was carrying a tall black crutch, though he was limping along without using it. Odom had six points and 14 rebounds.
The Lakers reached the NBA finals last season despite losing Bynum for the final 46 games with an injury to his left knee, but they missed his inside presence when they were overpowered by Boston in six games.
Gasol and Odom were too big for the undersized Knicks, but the Lakers will get a truer test of where they are without Bynum when they visit the Celtics and Cleveland Cavaliers later this week.
Al Harrington scored 24 points, David Lee had 22 points and 12 rebounds, and reserve Wilson Chandler added 20 points for the Knicks, who had won three straight and six of seven, but didn't have the firepower to stay with the Western Conference leaders in the opener of their brutally tough week.
New York hosts Cleveland on Wednesday and Boston on Friday. It's the first time a team has played three straight games against opponents with .750 winning percentages after Feb. 1 since the Celtics did it in February 1995, according to the Elias Sports Bureau.
Knicks coach Mike D'Antoni said the daunting slate would give the Knicks the chance to "elevate" their game.
"These will be three great games to do that and whatever happens we'll spin it the best way we can," D'Antoni said before the game.
Odom made a free throw 14 seconds into the game to open the scoring, then Bryant and Gasol combined for the next 30 Los Angeles points. Bryant's 3-pointer with 35 seconds left gave him 18 points and the Lakers a 31-26 lead headed to the second.
New York was down only one before Bryant returned from a break with 7:25 left in the half and took over the game. He scored nine points in a 1:15 span to make it 49-42 and had 16 points in the second quarter, giving Los Angeles a 65-54 advantage.
He hit the 40-point mark during a 15-4 spurt midway through the third quarter that allowed the Lakers to finally shake free of their Knicks.