A three-time Most Valuable Player, Favre was brilliant in his 166th consecutive start, especially in the first half when he completed 22 of 31 passes as the Packers built a 30-7 lead.
Favre, who suffered a strained knee ligament in his left knee three weeks ago, finished 26 of 39 for 351 yards and two touchdowns. It was his 35th career 300-yard game.
"The knee feels fine," said Favre, who moved past Joe Montana (40,551) and into sixth place on the all-time list for passing yards. "It's a little tight. The only time I felt it was when I tackled Terry Glenn in the end zone."
"He put on a clinic today," Lions Coach Marty Mornhinweg said. "You don't even have to make a cut-up on it, you just put the film on and the cut-up is already made. The guy was outstanding today."
Donald Driver caught 11 passes for 130 yards as the Packers (8-1) continued to set the pace as the NFL's best team. Green Bay has all but locked up the NFC North Division, holding a five-game lead over the Lions (3-6).
The Packers' winning streak is their longest in the regular season since 1963.
Joey Harrington completed 20 of 44 passes for 236 yards with two touchdowns and two interceptions for the Lions, who have lost their last 11 road encounters with Green Bay.
"When you have a guy like Brett Favre out there who can make so many plays, it's tough to play against him," Harrington said.
Harrington threw a beautiful 63-yard touchdown pass to Az-Zahir Hakim midway through the first quarter, giving the Lions a 7-3 lead.
But it was all downhill from there as the Packers exploded for 27 points in the second quarter.
Favre started the onslaught 25 seconds into the period, capping a nine-play, 64-yard drive by finding tight end Bubba Franks with a four-yard touchdown.
Ryan Longwell kicked field goals of 40 and 36 yards on the next two drives, making it 16-7 before the defense got into the act.
Operating deep in his own territory, Harrington had his pass deflect off the hands of former Packer Bill Schroeder and intercepted by rookie safety Marques Anderson, who scored on a 14-yard return to make it 23-7.
"Once again it seemed like I was just in the right place at the right time," Anderson said. "The first thing I did was make sure I caught it, but as soon as the ball was in my hands, I could smell the end zone."
Anderson also brought back an interception for a touchdown in the Packers' 37-31 victory at Detroit in September.
Schroeder had a terrible game in his return to Green Bay, failing to catch a pass while dropping three others, including the interception by Anderson. He had one of his drops on the game's final play in the end zone.
After stopping the Lions again, Favre and the offense went back to work again with a six-play, 68-yard drive.
Favre had completions of 10 and 12 yards to Driver before connecting with Terry Glenn for 46 yards to the one. Najeh Davenport plunged over from one yard with 17 seconds left in the half for a 30-7 advantage.
Green Bay dominated the entire half, garnering 18 first downs compared to two for Detroit while also holding a lopsided 345-120 advantage in total yards.
Favre is no stranger to big first halfs. He completed 17 of 25 passes for 287 yards and three touchdowns in the first half in a 34-21 victory at Chicago on a Monday night in October.
The only negative for the Packers is that both running backs, Ahman Green (neck) and Davenport (foot) suffered injuries.
Green Bay continued to pour it on after halftime. Longwell kicked a 33-yard field goal and Favre tossed a nine-yard touchdown pass to fullback William Henderson, making it 40-7.
Harrington threw a one-yard touchdown pass to Mikhael Ricks early in the fourth to cap the scoring.
James Stewart was a bright spot for the Lions, carrying 15 times for 122 yards.