With a 45-yard strike to Diontae Johnson on third down, Roethlisberger threw his 400th passing touchdown, joining an exclusive club that includes Packers quarterbacks Aaron Rodgers (418) and Brett Favre (508).
Other quarterbacks with at least 400 passing touchdowns are Tom Brady (591), Drew Brees (571), Peyton Manning (539), Philip Rivers (421) and Dan Marino (420).
Roethlisberger, 39, hit the mark in 237 career games.
With one milestone out of the way early, Roethlisberger finished the game by hitting another. With 232 passing yards in the loss to Green Bay, he surpassed Marino for sixth in all-time passing yards with 61,381.
The timing of the historical score was also significant for the Steelers, snapping a 13-game stretch without a touchdown on their opening possession. The last time they had scored a touchdown on their first drive was Week 7 against the Titans last year.
But it didn't help the offense set a tone. The 75-yard drive was the Steelers' longest of the day, and Roethlisberger finished completing 26 of 40 attempts with an interception.
"It was a good opening drive for us, we finally scored early," he said after the game. "Now we have to find a way to continue to score and move the ball. Eliminate the mistakes."