Brady finished 24-of-35 for 331 yards.
Julian Edelman scored on a punt return and hauled in five receptions for 58 yards with a touchdown for the Patriots (7-3).
Shane Vereen and Stevan Ridley each scored in the fourth quarter as AFC East-leading New England cruised to its fourth consecutive victory.
Andrew Luck, meanwhile, was picked off three times -- two of which were returned for touchdowns -- and lost a fumble for the Colts, negating his 334-yard, two-touchdown performance.
Indianapolis (6-4) saw its four-game winning streak snapped with the one-sided defeat.