Philip Rivers tossed three touchdown passes as San Diego handed Houston their first home loss of the NFL season with a 21-13 win at NRG Stadium.
The Chargers (5-6) won behind Rivers' pinpoint passing and a strong performance from their defense, which forced four turnovers.
Rivers finished 22 of 30 for 242 yards with TD passes to Dontrelle Inman, Tyrell Williams and Hunter Henry.
Elsewhere, Atlanta all but extinguished Arizona's flickering playoff hopes with a 38-19 victory over the Cardinals.
Taylor Gabriel raced 35 and 25 yards for touchdowns on screen passes from Matt Ryan and the Falcons improved to 7-4 over the Cardinals (4-6-1), who have dropped eight straight games at the Georgia Dome.
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Ryan completed 26 of 34 passes for 269 yards, and the Falcons rushed for three touchdowns and 118 yards to maintain their hold on first place in the NFC South.
Eli Manning threw three touchdown passes, including two to Odell Beckham Jr, as the New York Giants won their sixth straight game with a 27-13 victory over Cleveland.
The win allowed the Giants (8-3) to keep pace with the Dallas Cowboys (10-1) in the NFC East. The Browns (0-12) are the only winless team in the NFL.
In other games, Baltimore beat Cincinnati 19-14, Miami overcame San Francisco 31-24, New Orleans crushed Los Angeles 49-21, Tennessee held off Chicago 27-21 and Buffalo beat Jacksonville 28-21.
