The Cincinnati Bengals and their high-earning quarterback Joe Burrow suffered a surprise 24-3 defeat at divisional rivals Cleveland while the Tampa Bay Buccaneers started life after Tom Brady with 20-17 victory at Minnesota.
The 49ers, beaten in the NFC Championship game last season by the Philadelphia Eagles, made the perfect start with a convincing victory in Pittsburgh as quarterback Brock Purdy threw for 220 yards and two touchdowns.
After grabbing the starting role in his rookie season, Purdy underwent elbow surgery during the off-season but showed no signs of any lingering issues as he completed 19 of 29 passes.
Running back Christian McCaffrey also enjoyed a dominant opening day as he rushed for 152 yards and a touchdown.
San Francisco got themselves underway with Purdy's eight-yard touchdown pass into the endzone to Brandon Aiyuk and the same combination delivered again in the second quarter with Aiyuk brilliantly pulling in an 18-yard pass into the corner despite the close attention of Patrick Peterson.
The Steelers narrowed the deficit at the end of the first half when Pat Freiermuth collected a three-yard scoring pass from Kenny Pickett at the end of a 12-play, 95-yard drive.
But the 49ers defense held firm in the second half and McCaffrey's magnificent 65-yard rushing touchdown in the third quarter crowned an excellent win.
The other defeated conference championship team from last year, the Bengals - who lost out to eventual Super Bowl winners Kansas City in the AFC Championship - had a very different start.
Browns quarterback Deshaun Watson, who missed the first 11 games of last season after he was suspended following an investigation into sexual harassment allegations, threw one touchdown and ran for another in an impressive display from Cleveland.
Burrow struggles
Burrow signed a five-year contract extension with the Bengals on Saturday that makes him the league's highest-paid player, with the 26-year-old due to earn $275 million from the deal, but he was held to just 82 yards passing, the lowest return of his career.
Watson got the Browns rolling with a 13-yard touchdown run at the end of the second quarter and then sealed the victory with a three-yard pass to Harrison Bryant in the fourth, with the quarterback then running in the two-point conversion.
Tampa Bay had turned to Baker Mayfield to replace the retired Brady and after a sticky opening in Minneapolis he made a winning start for his new club.
Mayfield threw for 173 yards and two touchdowns - tying the game at 10-10 with a 28-yard pass to Mike Evans late in the second before a seven-yard pass to Trey Palmer, at the end of a 16-play, 75-yard drive in the third put Tampa ahead.
The Vikings fought back, with Kirk Cousins finding Alexander Mattison for a touchdown early in the fourth, but Tampa won the game on a career-long 57-yard field goal from Chase McLaughlin.
The Bucs defence then stood firm on the final two possessions for Minnesota.
