San Diego handed New England their first home loss since December 2002, a 22-game span, with a stylish 41-17 win.
Drew Brees threw for two TDs, LaDainian Tomlinson ran for two more and Antonio Gates had six catches for 108 yards.
Hurricane-hit New Orleans beat Buffalo 19-7 at their temporary home, the Alamodome in San Antonio.
Cincinnati are 4-0 for the first time since 1988 - the last time they went to the Super Bowl - after a tight 16-10 victory over Houston.
The defeat gave Texans their first 0-3 start in four seasons since they joined the league as an expansion team.
Peyton Manning threw for 264 yards and four TDs as Indianapolis (4-0) won 31-10 at Nashville.
Two of his touchdown passes found Marvin Harrison, tying the NFL record of 85 for most TDs between a quarterback and receiver.
They equalled the mark set by Steve Young and Jerry Rice for the San Francisco 49ers.
Joey Galloway scored on an 80-yard reception and Brian Griese threw for 302 yards as Tampa Bay beat Detroit 17-13 for their first 4-0 start since 1997.
Eli Manning threw for 296 yards and a career-high four touchdowns as the free-scoring New York Giants pounded St Louis 44-24.
In Mexico City, Josh McCown passed for 383 yards and two touchdowns as the Arizona Cardinals beat the San Francisco 49ers 31-14.
The first NFL regular season game played outside the United States attracted 105,000 fans to the Azteca Stadium.
Neil Rackers kicked six field goals for the Cardinals, while Anquan Boldin had eight catches for 116 yards.
The 49ers scored two touchdowns on fumble returns in the first quarter to take a 14-0 lead, but the Cardinals rallied for 31 unanswered points.
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