It was Manning's fifth consecutive 300-yard game, tying his personal best and setting a Denver franchise record.
The Broncos (4-3) put together consecutive wins for the first time this season. The Saints (2-5) saw their two-game winning streak end. The 20-point loss was New Orleans' biggest margin of defeat this season.
Willis McGahee also had a big night against the porous New Orleans defense, running for 122 yards and a touchdown on 23 carries. It was his 33rd career 100-yard rushing game, the most among active players.
Brees, who last faced Manning when he led the Saints to a win over Manning's former team, the Indianapolis Colts, in the Super Bowl following the 2009 season, couldn't repeat his past success.
He threw for 213 yards, completing 22 of 42 passes. Brees had touchdown passes of 29 yards to Darren Sproles and 18 yards to Jimmy Graham late in the game. He also had an interception that led to a Denver touchdown.
Up 17-7 at halftime, the Broncos stretched their lead behind an 11-play, 93-yard march that culminated in the short scoring pass to Thomas with 9:30 remaining in the third quarter.
Following a New Orleans punt, Manning got the Broncos' offense going again, hitting Jacob Tamme and Thomas with successive 23-yard completions to the Saints' 5-yard line. After a run by McGahee moved the ball to the 2, Manning found Decker open in the end zone on the first play of the fourth quarter, the second time the duo teamed up for a touchdown.
The game was Joe Vitt's first regular-season contest as the Saints' interim head coach following his return from his six-game "Bountygate" suspension. Saints head coach Sean Payton remains on suspension for the entire season.
Linebacker Jonathan Vilma also was active for a second consecutive game pending a hearing on his appeal of his year-long, NFL-imposed "Bountygate" suspension.
The Broncos broke a 7-7 tie on Manning's first touchdown pass of the night, and Matt Prater kicked the first of his two 33-yard field goals as time expired in the second quarter to give Denver a 17-7 halftime lead.
Earlier in the second quarter, linebacker Wesley Woodyard gave the Broncos a short field when he got in front of Graham and intercepted Brees' fourth-down pass near midfield. Manning connected with Thomas on the left side for a 34-yard gain, and three plays later, Manning found Eric Decker in the corner of the end zone for a 13-yard touchdown pass and a 14-7 lead. Decker celebrated the score with a Lambeau-like leap into the stands.
A turnover figured in the Saints' initial score. McGahee fumbled on a run up the middle, and linebacker Curtis Lofton recovered at New Orleans' 45-yard line. Three plays later, Darren Sproles split defenders to get open over the middle, and Brees found him for a 29-yard touchdown, leveling the score at 7.
The touchdown pass was the 300th of Brees' career, tying him for sixth all-time with Hall of Fame quarterback John Elway, now the Broncos' top football operations executive. Brees took sole possession of sixth place when he hit Graham for a touchdown with 2:03 remaining.
Backed up to their own 2-yard line after a punt early in the second quarter, the Broncos' leaned on McGahee to get them out of a hole. He advanced the ball 26 yards on four consecutive carries, and Manning then hit Thomas 41 yards downfield on a post pattern to give the Broncos a first down at the New Orleans 31-yard line.
McGahee got the ball close to the goal line with a 14-yard catch to the 1. He bulled his way in for the touchdown on the next play, behind a lead block from defensive tackle Mitch Unrein, who lined up at fullback.
NOTES: Thomas finished with seven receptions for 137 yards. ... The Broncos were without ailing cornerback Tracy Porter for a second consecutive game. A former Saint, Porter famously intercepted Manning in the Super Bowl three years ago to help New Orleans beat Indianapolis. Porter has been sidelined since he experiencing dizziness and a rapid heartbeat two weeks ago shortly before the Broncos boarded a plane to head to San Diego to play the Chargers. ... Chris Harris started at right cornerback in place of Porter. ... Linebacker Scott Shanle, who dealt with an illness earlier this week, was among the Saints' inactive players. ... Defensive tackle Brodrick Bunkley, a former Bronco who signed with the Saints in the offseason as a free agent, also was deactivated by New Orleans. ... Brees extended his NFL record by throwing a touchdown pass in a 50th straight game. ... Saints wide receiver Courtney Roby left in the second quarter with a shoulder injury. ... Denver linebacker Joe Mays left in the third quarter with an ankle injury.