The underdog Lions, hosting a Thanksgiving Day game for the 71st time, put up a battle through the first two periods and took a 17-10 advantage into halftime.
Brady then took over while leading the Patriots to 35 points over the third and fourth quarters.
He threw two touchdown passes each to Deion Branch and Wes Welker while putting together a perfect passing rating for the game. Brady completed 21-of-27 passes for 341 yards, carrying New England to its third straight win and a 9-2 record.
The Patriots are a half game in front of the New York Jets at the top of the AFC East.
Detroit lost on Thanksgiving for the seventh straight year and fell to 2-9 with their fourth consecutive setback.
Branch caught a 79-yard touchdown pass late in the third period that put the Patriots in front for good and added a 22-yard scoring reception in the fourth. He had three catches overall for 113 yards.
Welker, who gained 90 yards with eight catches, was on the receiving end of touchdown passes covering 5 and 16 yards.
Detroit's Shaun Hill was good on 27-of-46 passes for 285 yards with a touchdown and two interceptions.