O'Neill anticipates Nyquist winning at Churchill Downs this week being the start of a possible Triple Crown run. It would be the second straight time with a single winner in the Kentucky Derby, Preakness Stakes and Belmont Stakes. American Pharoah won the Triple Crown in 2015, the first since Affirmed in 1978.
"He took horse racing from the back page of the sports section, sometimes not even covered in the sports section, to the front page of the sports section," O'Neill said of American Pharoah. "I look forward to having Nyquist be on the front of the sports section."
American Pharoah finished fifth in his first race and then won four in a row before the Derby last spring.
Nyquist (7-0) arrives as a decorated favorite with wins at three Grade I stakes races, last accomplished in 1975, and won last year's Breeder's Cup juvenile. O'Neill trained 2012 Kentucky Derby winner I'll Have Another and said the draw -- Wednesday afternoon -- will be important. Very few of the 20 horses in the 2016 field have run the race distance of 1 1/4 miles.
"And then even if you get a clean trip, you've got to have a horse that can go a mile-and-a-quarter no matter what time it is. What I love about Nyquist's chances is he's won from the rail, he's won from the 12-hole, he's won wire-to-wire, he's won from just off the pace," O'Neill said.
Nyquist won the Florida Derby on April 2 and some of the same horses are running Saturday.
"A horse like Nyquist, you never seem to be able to get past them. If you run fast, he runs faster," said jockey Mike Smith, who is riding Danzing Candy on Saturday.