Sanders also caught nine passes for 76 yards and was instrumental in all three late scoring drives.
Sanders gained only 46 yards through the first three quarters, but finished with 116 in 25 carries.
"He's the best back in football right now and it's impossible to contain him for 60 minutes," Viking Coach Jerry Burns said. "But I thought we did as good a job as we could."
The Lions (5-1) are off to their best start since 1980, and with Chicago losing to Washington, they took sole possession of first place in the NFC Central Division.
It's the Lions' first time at the top since the end of the 1983 season. Their only loss, a 45-0 rout at Washington in their opener, came when Sanders was sidelined with an injury.
It was the fourth consecutive 100-yard game for Sanders. The only other player in Lion history with four consecutive 100-yard games was Billy Sims in 1983.
The Lions controlled the ball for 31 minutes 37 seconds, marking the fifth consecutive game they have held the ball more than 30 minutes.
The Vikings (2-4) led, 20-3, with 8:38 left in the fourth quarter on the second field goal by Fuad Reveiz. But the Lions stormed back with a 68-yard touchdown pass play from Rodney Peete to Robert Clark, a 16-yard touchdown pass to Willie Green and Sanders' decisive touchdown.
The Vikings' Rich Gannon, making his first start this year, completed 10 of 23 passes for 105 yards, including a two-yard touchdown pass to Steve Jordan.
"I thought at times Gannon played well," Burns said. "At other times, I didn't think he played as well as he could."
The Vikings also played without Herschel Walker, who had a bruised left shoulder.
"I decided before the game to keep him out of the game," Burns said. "I wasn't going to play him because his shoulder was in bad shape. The way things were going, I really didn't feel the need to put him in."
Peete completed 24 of 38 for 281 yards and two touchdowns. Sanders did the rest.
On the fourth snap of the game, Detroit's Mel Gray returned a punt 70 yards for an apparent touchdown. But it was called back because of an illegal block by Kevin Scott.
Four plays later, Minnesota's Leo Lewis returned a punt 44 yards to the Detroit 24-yard line. Four plays after that, Darrin Nelson swept left end for a touchdown and a 7-0 lead.