The American left-hander holed a 10-foot birdie putt on the 18th green to move three shots clear of Britain's Lee Westwood who was on level par with three holes to play.
Mickelson, who started the day on two over, birdied the fifth, ninth, 13th, 14th, 17th and 18th holes and had just one bogey on his card at the 10th.
Unless Westwood picks up three shots over the closing three holes, Mickelson will win his fifth major title and his first British Open.
(Editing by Tony Jimenez)
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