Never threatened down the stretch, the co-favourite won with a time of 2:03.59 before a crowd of some 170,000 that packed the grandstands and infield of Churchill Downs on a day that alternated between sunshine and rain.
Lookin at Lee, a 33-1 longshot, was second, 2 3/4 lengths back, in the first leg of U.S. thoroughbred racing's Triple Crown series for three-year-olds. Battle of Midway, another unfancied entry at 40-1, was third, 7 3/4 lengths off the pace.
Always Dreaming, who went off at 9-2 along with Irish War Cry, ran a dream race unflustered by the messy conditions caused by rains on Friday and Saturday.
Pletcher and Velazquez, record money winners among trainers and jockeys, added a long-awaited second Derby triumph to their respective resumes.
Velazquez followed up his 2011 winning ride aboard Animal Kingdom, while Pletcher added to his 2010 victory with Super Saver after previously saddling 45 horses in all at the Derby.
"We've run a lot of horses in it, and some of them may not have run so well," said Pletcher. "But in 17 years we have two wins, two seconds and three thirds so it's become a little more respectable now."
Velazquez, who had been out of the top nine in the Derby the last four years, said: "This was the best horse in the Derby and he proved it today.
"Once he got in a comfortable position I just waited until the quarter poll when I asked him to run."
Early favourite Classic Empire finished fourth, one length out of the money, while fancied McCraken finished eighth and Irish War Cry was 10th across the line, 16 1/2 lengths back.
UAE Derby winner Thunder Snow bucked out of the starting gate and was immediately pulled up in the opening moments of the race. The Irish-bred colt made it back to the barn under his own power and did not appear to be injured.
Another of Pletcher's three entries in the race won some surprise backing of the punters.
Patch, whose left eye was removed last year after an extreme inflammation, became a sentimental favourite, going from 30-1 in the early odds to 12-1 by race time before finishing 14th in the 20-horse field.
Always Dreaming paid $11.40, $7.20, $5.80 for a $2 bet. Lookin at Lee, a 33-1 shot, returned $26.60, $15.20, while 40-1 choice Battle of Midway paid $20.80.
(Reporting by Larry Fine in New York; Editing by Andrew Both/Peter Rutherford)
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