Ryan Tannehill threw for 319 yards and one touchdown Sunday, and the Dolphins defense held off yet another Colts' comeback bid for a 24-20 victory.
Charles Clay gave Miami the lead for good with a 1-yard TD run late in the third quarter. The Dolphins are 2-0 for only the second time since 2004.
Indianapolis (1-1) lost at home for the first time in 12 months and only the second time in Andrew Luck's brief NFL career.
Luck had the Colts positioned to rally yet again after reaching the Miami 23-yard line with 1:45 left in the game.
But this time, Luck threw three straight incompletions and then could not evade the Dolphins pass rush on fourth down, allowing Miami to run out the clock.
Tannehill finished 23 of 34.
Luck was 25 of 43 for 321 yards with one TD and one interception.
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