It was also a second successive major success for the Californian, then aged 35, following his US PGA Championship triumph the previous August.
Mickelson had three victories in nine majors having been winless in 46 prior to that.
He regained the green jacket after posting a final-round 69 to move to seven under for the tournament, having held off a series of challenges in a fine display of front-running.
South African Clark achieved his best-ever finish in a major with his second place, while defending champion Tiger Woods was joint third with Retief Goosen, Chad Campbell, Fred Couples and Jose Maria Olazabal.
Mickelson, who had taken a one-shot lead into the final day, said: "I will cherish that final round and look back at some of the shots I was able to pull out and some of the putts I was able to make.
"It was a long day, but a wonderful day."
Mickelson was three shots clear when he stood on the final tee, and he said: "I loved it. It was incredible. I had actually been wanting a four or five-shot lead, but three was OK too."
Mickelson would go on to claim the title for a third time in 2010, and subsequently secured his fifth major triumph by winning the 2013 Open Championship.