Quarterback Josh Allen threw for a touchdown and rushed for two more as the Buffalo Bills thrashed the Minnesota Vikings 27-6.
Allen completed 15 of his 22 passes for 196 yards, but it was on the ground where he did most of the damage as the previously winless Bills pulled off a shock result in Minneapolis.
The Vikings were shut out until the final quarter, when Kirk Cousins found Kyle Rudolph in the end zone for a consolation touchdown.
New Orleans quarterback Drew Brees was also the star of the show as the Saints beat the Atlanta Falcons 43-37 in overtime.
With a 17-yard completion to wide receiver Michael Thomas in the second quarter, Brees moved ahead of Brett Favre with 6,301 career pass completions, an NFL record.
And the 39-year-old was not finished there, making a total of 39 completions as he threw for three touchdowns and then ran in the vital scores himself to first force overtime and then seal victory.
Records were also broken elsewhere as Kansas City Chiefs quarterback Patrick Mahomes led his side to a 38-27 victory over the San Francisco 49ers.
Leading the Chiefs to the end zone on each of his five first-half possessions, Mahomes notched his 13th touchdown pass of 2018, breaking Peyton Manning's mark for most passing scores in the first three games of a season.
And a bad day for the 49ers was made worse when quarterback Jimmy Garoppolo suffered a suspected ACL injury during the fourth quarter. Garoppolo will undergo an MRI on Monday to confirm the severity of the injury.
Matt Patricia saw his Detroit Lions team overcome his previous employers the New England Patriots 26-10 as the side recorded their first win of the NFL season.
Patricia, who was part of three Super Bowl wins for the Patriots as offensive assistant and defensive coordinator, became head coach of the Lions in the off-season.
Patriots quarterback Tom Brady had a relatively quiet night, the Lions restricting him to 129 yards, with the 40-year-old only throwing for a single touchdown.
Matthew Stafford had 262 yards and two touchdowns, while the Lions' ground game was supported by Kerryon Johnson who had 101 rushing yards.
The Denver Broncos had running back Phillip Lindsay ejected in the first half of his side's 27-14 loss to the Baltimore Ravens after he threw a punch while in a pile of players battling for possession of the ball.
Ravens quarterback Joe Flacco threw for a touchdown and Alex Collins and Javorius Allen rushed for the home side's other TDs.
Miami Dolphins defensive tackle Akeem Spence was also ejected during the second quarter of the game against the Oakland Raiders.
Spence was dismissed for pulling off Raiders guard Kelechi Osemele's helmet following a scuffle, but the Dolphins recovered from 17-7 down to win 28-20, with Jakeem Grant scoring two touchdowns while Albert Wilson had long-range receiving and passing scores.
The Jacksonville Jaguars suffered their first defeat of the season in a 9-6 home loss to the Tennessee Titans, who lost quarterback Blaine Gabbert to injury after he was sacked in the first quarter.
And the Cincinnati Bengals' unbeaten record also disappeared as they lost 31-21 at Carolina, Panthers quarterback Cam Newton throwing for two touchdowns and running for two more.
Adrian Peterson rushed for two touchdowns as the Washington Redskins beat the Green Bay Packers 31-17, while Super Bowl champions the Philadelphia Eagles edged past the Indianapolis Colts 20-16.
In the battle of teams who started the day without a win, the New York Giants came out on top against the Houston Texans, Eli Manning completing 25 of his 29 pass attempts for 297 yards and two touchdowns.
In the late games, the Rams won the battle of Los Angeles in a 35-23 win over the Chargers, with Jared Goff passing for three touchdowns and 354 yards, the Chicago Bears condemned the Arizona Cardinals to their third straight loss 16-14, and Russell Wilson had two touchdowns in a 24-13 victory over the Dallas Cowboys.