Celebrity news website TMZ said he died after suffering a seizure at Chicago's Midway airport on Sunday morning.
The Cook County Medical Examiner's Office said the cause was unknown.
Juice Wrld, real name Jarad Anthony Higgins, was best-known for his viral 2018 hit Lucid Dreams. Mental health, mortality and drug use were common themes in his music.
His record label, Interscope Geffen A&M Records, said Juice Wrld was an "exceptional human being" who "made a profound impact on the world in such a short period of time".
Chicago police told the BBC a 21-year-old man suffered a medical emergency at around 02:00 local time (08:00 GMT) and was taken to hospital, where he was pronounced dead.
Anthony Guglielmi, a police spokesman, told the Chicago Sun Times there were "no signs of foul play" and it was unclear whether drugs played a role in his death.