Miami will play fourth-seeded Atlanta in the first round of the playoffs.
Wade shot 19-for-30 from the field, set a career high with six 3-pointers, and nearly topped Glen Rice's record of 56 points before leaving with 1:06 remaining.
Michael Beasley finished with 28 points and 16 rebounds for the Heat, who also got 15 points from Mario Chalmers.
Al Harrington and Tyson Chandler each scored 21 points for New York. Quentin Richardson finished with 14 and David Lee had an 11-point, 11-rebound night for the Knicks.
Wade scored for the final time with 5:31 remaining. Only then did the Knicks figure out how to stop him, well after it was too late.
Wade's MVP candidacy is so important to the Heat that the franchise took the step - rare for them - of campaigning for the award. Last week, the team sent out a promotional DVD to postseason award voters.
Now, it's already outdated. This might have been the best show of the season.
He was diving on the floor for loose balls, finished with nine rebounds, and dominated the Knicks in Miami for the second time this season.
It was the 11th 50-point game in the NBA this season, the third by Wade - matching Cleveland's LeBron James for the league's high - and the third against the Knicks. Kobe Bryant got the NBA season-best point total with 61 in Madison Square Garden on Feb. 2, and James scored 52 at New York's famed arena two nights later.
Wade now has six of the eight highest-scoring games in Heat history, four of them this season.
Consecutive 3-pointers by Wade late in the third quarter put Miami up 95-87. He reached 50 points on an 8-footer with 26.4 seconds left in the third quarter, meaning the Heat entered the final period leading by six, and with the rest of Wade's teammates trailing him by three.
Yes, through three quarters, it was Wade 50, Rest of Heat 47.
He became the first player since Bryant to score 50 before the fourth quarter began. Bryant did it Nov. 30, 2006 against Utah, getting 52 through three periods and not playing in the fourth, according to the Elias Sports Bureau.
The Knicks' season ends Wednesday, and accordingly, they played a loose style.
Larry Hughes intercepted a pass at one end, dribbled the other way and spun a behind-the-back flip to Chris Wilcox - who ran over Heat forward James Jones on his way to a three-point play that drew New York within 37-32 with 11:08 left in the half.
That was part of a big second quarter by the high-octane Knicks, who trailed by as many as 14 points in the first half before getting going.
New York managed only 17 points in the game's first 9½ minutes, then put up a staggering 48 points in the next 14½, taking a 65-63 lead into intermission. The Knicks shot 68 percent in the second quarter alone, with Harrington getting 15 points in one seven-minute stretch of the period.
And yet, they couldn't pull away, simply because they couldn't stop Wade.
Miami's MVP hopeful - "MV3" they're now calling him, a nod to his jersey number - had 27 points by halftime on 10-for-14 shooting, even though he spent the first 5½ minutes of the second quarter on the bench.
Everything Wade shot seemed like it went in, even a behind-the-backboard attempt midway through the third quarter during a stoppage after a foul. It swished, didn't count, and the crowd cheered anyway.
Notes: Wade's big night got started with a 16-point first quarter, which was his highest-scoring period since putting up 19 in the first quarter against Phoenix on March 4. ... The Knicks finished with a 12-29 road record. ... Miami Dolphins coach Tony Sparano was courtside, a couple of seats away from the Heat bench. Actor Jeffrey Donovan, the star of "Burn Notice," was also in the crowd.
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