It was Crosby's third four-point game in a season in which concussion troubles have limited him to 18 games. And it came after he was held without a point in his past two outings and a day after his nose was bloodied by a puck in a 5-3 loss at the New York Islanders.
Steve Sullivan had a goal and two assists, Evgeni Malkin had a goal and assist, and Pascal Dupuis set up two to extend his points streak to an NHL season-best 13 games. Pittsburgh (48-24-6) rebounded from two straight losses to the Islanders and moved four points ahead of fifth-place Philadelphia in the Eastern Conference standings.
The Sabres (38-30-10) had a five-game winning streak snapped, and dropped into ninth place, behind the Washington Capitals. Both teams have four games left and 86 points, but the Capitals hold the tiebreaker edge.
The Sabres' loss also allowed the idle Boston Bruins to clinch a playoff berth.
Thomas Vanek, Tyler Ennis and Jordan Leopold scored for the Sabres, who dropped to 14-3-4 in their past 21, and lost for the first time in regulation in 10 games (7-1-2).
The Sabres squandered a golden opportunity to at least earn a point in the final 2:21, when Malkin was penalized for delay of game after his clearing attempt sailed into the stands.
Vanek had two solid chances in front in the final 25 seconds, only to be turned away before Jordan Staal sealed the win by scoring into an empty net.
Crosby became the NHL's seventh youngest player to reach the 600-point plateau, and he did it in the seventh-fewest games. Crosby now has 220 goals and 381 assists in 430 career games. At 24 years and 236 days, Crosby is the youngest player to hit the mark since Pierre Turgeon did it with the Islanders in 1994.
Crosby had a hand in all four goals in a game the Penguins never trailed, and built a 4-2 lead on Sullivan's tip in goal in front with 4:54 left in the second period.
After getting the secondary assist on Malkin's game-opening power-play goal 3:50 in, Crosby scored some 10 minutes later by sweeping a puck in through Ryan Miller's legs while parked to the right of the net.
Driving up the right wing, Crosby then made a perfect feed through the middle in setting up James Neal's power-play goal 11:43 into the second period. And Crosby wasn't done yet, chasing down a loose puck to the left of the net in helping set up Sullivan's goal 3 minutes later.
The Penguins won despite backup goalie Brent Johnson's ongoing struggles in making his first start after missing 19 games with an undisclosed injury. And it was his first game since being pulled after allowing three goals on 12 shots in 23 minutes of a 6-2 loss at Buffalo on Feb. 19.
Johnson made 25 saves, but had difficulty handling the puck.
Johnson failed to control Jason Pominville's initial shot, allowing the puck to fall in front of him, where Leopold swept it in to tie a goal apiece 6:35 in.
Johnson looked even worse on Ennis' goal 10 minutes later. Ennis drove across the blue line and worked his way into the right circle where, using defenseman Zbynek Michalek as a screen, snapped a shot that went in off the inside of Johnson's far pad and in to tie it at 2.
Johnson did come up big in stopping Derek Roy set up alone in front with 2:15 left in the first period, but he was obviously battling the puck, including whiffing on Ville Leino's shot from the left boards early into the second. Midway through the third period, Johnson trapped the puck to the ice with his glove, then inexplicably let it go before the whistle with Vanek standing in front of him. Johnson recovered in time to stop Vanek's shot.
Johnson didn't have a chance on Vanek's goal scored cutting the lead to 4-3 with 3:01 left in the second period. That's when Pittsburgh defenseman Brian Strait's clearing attempt from the corner took a wild bounce off the glass and landed at Vanek's feet directly in front of the net.
Notes: Penguins D Matt Niskanen returned after missing four games with an upper-body injury, and C Joe Vitale returned after missing seven games with an upper-body injury. ... The Sabres, who play at Toronto on Saturday, opened their NHL-high 21st and final set of playing games on consecutive nights. Buffalo entered the night 13-7-0 in the first game, and 7-8-5 on the following game. ... The Penguins close their season playing three of their final four games at home. ... The Sabres announced their season-ending awards, as voted by the players. Captain and leading goal-scorer Pominville was selected the MVP, backup G Jhonas Enroth rookie of the year and RW Patrick Kaleta unsung hero.