Medina Spirit, listed as 12-1 odds at post time, gave trainer Bob Baffert his record seventh Kentucky Derby win.
Favorite Essential Quality, previously unbeaten as a 3-year-old and a 3-1 favorite at post time, finished fourth.
In 2020, the Derby was moved to September because of the coronavirus pandemic and was second in the Triple Crown lineup after the Belmont Stakes.
Last year, there were no fans in the stands at Churchill Downs for the Derby, which regularly brings a crowd of more than 150,000 to the track, The New York Times reported.
In addition to the changed date, there was a shift in tone last year.
No Black jockeys rode in the race between 1921 and 2000, according to Smithsonian Magazine; the last Black rider to win the Derby was Jimmy Winkfield in 1901 and 1902.
For the first time, the Derby was run without horses using the anti-bleeding drug Lasix, The Associated Press reported.
There was another shift in tone last year.