Three touchdown catches from Antonio Gates inspired the San Diego Chargers to an upset 30-21 win over the Seattle Seahawks.
At a hot and steamy Qualcomm Stadium, Gates equalled his career-high TD receptions in one game as the Chargers controlled the tempo and possession against on out-of-sorts Seahawks.
The visitors did give themselves a chance at the end of the third quarter when Russell Wilson threw a 14-yard touchdown to Marshawn Lynch in a play that cut the Chargers' lead to six, but victory was confirmed for the home side when Nick Novak slotted a field goal late in the fourth.
Robert Griffin III suffered yet another injury as the Washington Redskins cruised to a 41-10 win over the Jacksonville Jaguars.
The star quarterback dislocated his left ankle in the first quarter of the clash, with reports suggesting the incident could spell the end of the 24-year-old's season.
The Redskins were able to collect their first win of the new season without him, with replacement Kirk Cousins throwing for 250 yards and managing two touchdown passes in the rout.
A last-second field goal from Billy Cundiff lifted the Cleveland Browns to a stunning 26-24 win over the New Orleans Saints, leaving the latter winless after two games.
A Mark Ingram-touchdown with 12 minutes left looked to have been enough for the Saints as they went ahead 24-23, but Cundiff kicked true from 29 yards with three seconds left on the clock to see the Browns win their home opener for the first time in 10 years.
Jay Cutler threw three touchdown passes in the fourth quarter as the Chicago Bears piled on 21 points to surge past the San Francisco 49ers 28-20 at Levi"s Stadium.
The Giants went into the last quarter ahead 20-7 and looked certain to move 2-0 for the season but Cutler had other ideas, finding Brandon Marshall twice and Martellus Bennett once to give the Bears a memorable win.
The Buffalo Bills bested the Miami Dolphins 29-10 to get off to a 2-0 for only the sixth time since 2000, while the Green Bay Packers rallied from an 18-point deficit to topple the New York Jets 31-24.
Greg Zuerlein's four field goals lifted the St Louis Rams over the Tampa Bay Buccaneers 19-17, the Dallas Cowboys cruised past the Tennessee Titans 26-10 and the Arizona Cardinals proved they can live without starting quarterback Carson Palmer as they saw off the New York Giants 25-14.
The New England Patriots looked ominous as they crushed the Minnesota Vikings 30-7 while the Houston Texans won their second straight game to open the season, beating the Oakland Raiders 30-14 thanks to a dominant display in the opening three quarters.
The Cincinnati Bengals overcame the loss of receiver AJ Green to beat the Atlanta Falcons 24-10 as they moved to 2-0 for the season, the Carolina Panthers saw off the Detroit Lions 24-7 and the Denver Broncos held firm late to record a 24-17 win over the Kansas City Chiefs.