Writing an epic conclusion to a week of domination at Augusta National, the 21-year-old American fired a two-under par 70 to finish on 18-under 270, matching the 72-hole tournament record set by Tiger Woods in 1997.
"It's the most incredible week of my life," Spieth said.
"It's a dream come true. I'm still kind of in shock a little bit."
Spieth claimed the green jacket symbolic of Masters suprmeacy and the top prize of $1.8 million at the $10 million event by denying two of golf's top Major Champions another crown.
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England's Rose, the 2013 US Open winner and Spieth's last-pair playing partner, shot 70 to share second on 274 with 44-year-old US left-hander Mickelson, a five-time major winner who shot 69.
"I played a good solid round but I needed something exceptional. I just didn't quite get it," Mickelson said. "I just got outplayed. Jordan played great."
Top-ranked Rory McIlroy, seeking a third consecutive major win to complete his career Grand Slam, was fourth on 276 after a 66, one stroke ahead of Japan's Hideki Matsuyama.
"Considering where I was... I'm really proud of it," Woods said of his effort.
Spieth was a runner-up to Bubba Watson last year in his Masters debut after squandering a front-nine lead on Sunday, but this time responded four times when dropping a shot to his rivals, restoring his margin each time on the very next hole.
"Every time, I thought there was a chink in the armour, he would come up with a big putt," Rose said.
Also, Spieth became only the fifth wire-to-wire winner in Masters history, joining Craig Wood in 1941, Arnold Palmer in 1960, Jack Nicklaus in 1972 and Ray Floyd in 1976.
"It was awfully impressive," McIlroy said of Spieth's performance. Starting with a four-stroke lead after setting the 36- and 54-hole Masters scoring records, the youngest 18-hole leader in Masters history answered every stumble quickly.