Drew Brees led the way as NFC South leaders the New Orleans Saints won their eighth straight game with a 51-14 victory over the Cincinnati Bengals.
The quarterback completed 22 of 25 passes for 265 yards and three touchdowns and ran for another score.
His 17-yard touchdown to Michael Thomas at the end of the first half gave him 509 career touchdown passes, moving him ahead of Hall of Famer Brett Favre into second place in the NFL record books.
New England Patriots quarterback and three-time NFL MVP Tom Brady was stunned by the Tennessee Titans as they clinched a 34-10 win at Nissan Stadium.
The Titans sacked him three times and had multiple hits, while Brady completed just 21 of 41 passes for 254 yards and left the game in the fourth quarter.
The Patriots lost to Tennessee for the first time since 2002.
Patrick Mahomes threw for 249 yards and two touchdowns to power the Kansas City Chiefs to a 26-14 win over the Arizona Cardinals.
His 14-yard pass to Tyreek Hill in the second quarter gave him his league-leading 31st touchdown of the year.
Cardinals wide receiver Larry Fitzgerald passed Terrell Owens for second place in the most receiving yards in NFL history, and now stands on 15,952 for his career.
Meanwhile, the Cleveland Browns snapped a four-game losing streak by beating the Atlanta Falcons 28-16, while NFC North leaders the Chicago Bears defeated division opponents the Detroit Lions for the first time in two years, claiming a 34-22 victory.
The Washington Redskins toppled the Tampa Bay Buccaneers 16-3, with Alex Smith throwing six yards to Josh Doctson for the game’s only touchdown in the fourth quarter.
And the defending Super Bowl champions the Philadelphia Eagles suffered a third straight loss at home, falling 27-20 to the Dallas Cowboys.
Elsewhere, the Buffalo Bills outlasted the New York Jets 41-10, the Los Angeles Chargers took a sixth win in a row as they routed the Oakland Raiders 20-6 and the Los Angeles Rams beat the Seattle Seahawks 36-31.
Aaron Jones ran for career highs of 145 yards and two scores to help the Green Bay Packers defeat the Miami Dolphins 31-12, and the Indianapolis Colts edged their AFC South rivals the Jacksonville Jaguars 29-26.