Keselowski, who also claimed a victory at Bristol in August, took over the lead from Matt Kenseth with 111 laps remaining and held on to win the Food City 500.
Keselowski fended off several challenges by Kenseth over the latter stages of the race and posted an 0.7-second margin of victory at the finish line for his fifth career series win.
Five-time Bristol winner Kyle Busch was among those caught up in a seven-car crash early the in the contest.
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