Andre Iguodala had 18 points and a career-high 16 assists, and Jodie Meeks scored 14 for the Sixers, who are trying to catch the Knicks for sixth place in the Eastern Conference.
The Knicks seemingly had the game under control in the fourth until they self-destructed during a scoreless stretch that lasted more than 6 minutes and let the Sixers race into the lead.
Brand scored 19 points in the first quarter, then chipped in with big buckets in the fourth to send a crowd of nearly 20,000 into a frenzy.
Raymond Felton led the Knicks with 26 points and Amare Stoudemire had 21. Danilo Gallinari had 18 points and 13 rebounds.
Shawne Williams' 3 in the final seconds made it 100-98, but he missed the game-tying shot as the clock expired.
The Knicks lost their sixth straight road game. The rematch of the home-and-home series is Sunday.
The Knicks took control in the third quarter behind Felton's stellar performance, then completely collapsed for most of the fourth.
Brand's putback off his own miss and Thaddeus Young's one-handed dunk off Lou Williams' miss made it a one-point deficit. Lou Williams had a steal and slam for an 87-86 lead and Iguodala buried his first 3 of the game, quickly turning a five-point hole into a four-point lead.
Brand swished a jumper for a season-high 29 points and Iguodala followed with a pull-up jumper.
Then a bigger rarity: A nearly full house was rocking again for the Sixers heading into a timeout.
Felton ended the run and a 6 minute, 17-second scoreless stretch with a basket.
The Knicks hold a two-game lead over Philadelphia for sixth place in the Eastern Conference standings. It was about as big a game two teams with a combined 48 wins in February could play, especially in a city where NBA enthusiasm has been dormant.
Knicks coach Mike D'Antoni was talking playoffs before the game. He doesn't care if the Knicks are the sixth, seventh or eighth seed, as long as they're playing in the postseason. Sixers coach Doug Collins, who early last month was showing his team conference standings as a motivational ploy, insisted he wasn't thinking about any game beyond the Knicks.
He is glad the 76ers are least in the playoff conversation after a 3-13 start.
"All of a sudden, people are talking about us with a sense of relevancy," he said.
No coincidence, Brand's comeback has coincided with Philadelphia's.
Brand about had the game of his Sixers career in one quarter, making 7-of-8 shots for 19 points. The Sixers made 12 of their first 16 shots and raced to a 14-point lead.
The bulk of the buckets came courtesy of Iguodala. He had 10 assists and no points at one point in the second quarter and didn't make his first field goal until the third.
Knicks fans flocked to Philadelphia, serenading Stoudemire with "MVP!" chants and they roared over the muted Sixers faithful on Timofey Mozgov's thunderous dunk that capped a comeback for a 40-39 lead. They led 52-51 at the break.
Then the Knicks got rolling.
Tony Battie bobbled a pass under the basket, and Gallinari grabbed it and went the length of the court for a layup and a 74-67 lead. Felton hit two 3s in succession and the Knicks started creeping away with the lead.
Felton was phenomenal in the third with 15 points and helping the Knicks lead 82-73.
It just wasn't enough.
Notes: Knicks F Wilson Chandler scored three points after missing three games with a sore left calf. ... The Sixers are 20-13 after a 3-13 start.