The Lions improved to 14-2 and matched Minnesota atop the NFC North division, setting the stage for a showdown between the two clubs next week in Detroit to decide the top seed for the NFC playoffs.
The Lions have the NFL's top-scoring offensive unit, but their defensive side has been riddled by injuries and struggled again to stop the 49ers.
Goff and San Francisco's Brock Purdy, who threw for a career-high 377 yards and three touchdowns and ran for another score, combined to complete their first 15 passes as offences dominated and Detroit rallied as the second half began.
Goff flipped a 6-yard touchdown pass to Sam LaPorta and a 2-point conversion pass to Tim Patrick after 5:02 of the third quarter to lift the Lions level at 21-21.
The Niners (6-10) responded as Purdy threw a 5-yard touchdown toss to Deebo Samuel, but Detroit's Jake Bates kicked a 57-yard field goal to tighten the margin.
After Kerby Joseph intercepted a Purdy pass, the Lions grabbed their first lead of the game as Goff threw a 4-yard touchdown pass to Amon-Ra St. Brown and Detroit led 31-28.
Bates added a 42-yard field goal to boost the Lions' lead and Joseph made another pickoff, his ninth of the season, to kill a 49ers drive.
The turnover set the stage for a 30-yard touchdown run by Jahmyr Gibbs and despite a missed conversion kick, Detroit owned a 40-28 edge with 2:58 remaining.
Joshua Dodds scored on a 7-yard run for the Niners with 43 seconds remaining to create the final margin.
Next week's Lions-Vikings winner will capture a first-round bye and home-field advantage throughout the NFC playoffs while the loser will be a wildcard fifth seed and spend the playoffs on the road.
No teams in NFL history will have played a season finale with so many combined triumphs.