Despite missing the All-Star game with a left knee injury, Sidney Crosby picked up a goal and three assists and Jordan Staal also lit the lamp for the Penguins, who began their post-break slate with a victory and have won three of four.
Marc-Andre Fleury stopped 32 shots for his 16th win of the season.
Nikolai Zherdev and Marc Staal provided the scores for the Rangers, who lost for the second time in their last seven.
Fresh from a shelling in the All-Star game on Sunday which saw the Swedish netminder give up six goals on 21 shots, Henrik Lundqvist allowed all six goals on 33 shots in defeat.
Pittsburgh took a 2-1 lead 1:11 into the third period on a fluky goal from Staal, then Letang made it a two-goal Pens lead at 6:18, with a rising wrister from the outer edge of the right circle.
Midway through, Pittsburgh had a 5-on-3 advantage for 53 seconds, and Sykora made the Rangers pay by one-timing a shot off a Crosby feed through Lundqvist's pads at 10:01 for a 4-1 advantage.
Staal stuck a wrister high over Fleury's glove with 6:05 remaining to bring New York within two, but Letang restored the three-goal bulge by holding off a pair of defenders and slipping a low shot home with 3:39 to play.
Crosby finished off the goal explosion with 1:40 remaining, placing a perfect shot from a sharp angle into the net where the right post meets the crossbar.
Zherdev opened the scoring 2:24 into the contest, tucking home a shot before a diving Fleury could cut off a pass from Brandon Dubinsky.
Sykora evened the score at 6:35, managing to get his stick on a bouncing puck in the crease for a shot which caromed off Chris Drury's arm and into the net.
A scoreless second period saw Fleury stop all 18 shots he saw and Lundqvist had a relatively easy time, with eight saves.