After missing the majority of the last season with an elbow injury, the 38-year-old overcame a slow first quarter to throw for three touchdowns and 229 yards.
The quarterback was aided by a rampant Steelers defence which held New York's elite running back Saquon Barkley to just six yards from 15 carries.
Juju Smith-Schuster was the recipient for two of Pittsburgh's touchdowns while Giants quarterback Daniel Jones finished with two touchdowns and two interceptions.
Meanwhile the Tennessee Titans continued to be haunted by the field goal issues that plagued them last year, despite eking out a 16-14 victory against the Denver Broncos.
The Titans made just 18 field goals last season, but had faith that veteran kicker Stephen Gostkowski would be the man to turn their fortunes around.
But the 36-year-old was unable to get the team's season off to a better start as he missed three crucial field goals which kept Denver in the game.
He ultimately managed to shake off the curse when it mattered most, converting a 25-yard attempt with just 20 seconds remaining to help the Titans clinch the two-point win.