Manning added two more TD passes in the third quarter to lead Indianapolis to a 41-9 win over Detroit.
Dan Marino had a four-game streak in 1984, when he also set a league mark with 48 TD passes in a season, another milestone Manning is chasing.
"When he's retired, they'll compare everybody to Peyton Manning, without a doubt," Colts receiver Brandon Stokley said.
Manning connected with Stokley for three scores before breaking Marino's record with a TD pass to Marvin Harrison to help the Colts take a 27-9 lead at halftime. Manning has thrown at least three touchdowns in the first half in five of 11 games this season.
Manning finished 23-of-28 for 236 yards and zero interceptions for the AFC South-leading Colts (8-3).
The Colts replaced Manning with Jim Sorgi late in the third quarter, a move that denied Manning a chance at tying the NFL record of seven touchdown passes in a game shared by five players -- Sid Luckman, Adrian Burk, George Blanda, Y.A. Tittle and Joe Kapp.
Manning matched the team record he set in September 2003 against New Orleans, his father's former team. Before that performance, no one had thrown for six TDs in an NFL game in a dozen years.
With five regular-season games left, Manning has already matched Kurt Warner for third most TD passes in a season. Marino threw 44 TDs in 1986.