The passenger, who may have been shot multiple times, was taken to a hospital and pronounced dead following the incident that began around 2:45 a.m. MT (4:45 a.m. ET), said Denver police spokesman Sonny Jackson.
The driver was also treated at the hospital for unspecified wounds and released into police custody, Jackson said, adding that investigators "can't speculate what went on in the car."
Neither the driver nor the victim were immediately identified.
Police shut down a portion of the southbound lanes of Interstate 25 through the morning rush hour, causing massive gridlock,
as they sought to interview other drivers who may have witnessed the shooting.
Jackson said authorities were in contact with Uber and it was unclear if the shooting occurred while the driver was on a job. Prosecutors had not announced any charges as of early Friday morning.
In a 2016 case in Kalamazoo, Michigan, an Uber driver was charged with fatally shooting six people and wounding two others - apparently at random - and blaming the car service's mobile app for turning him into "a puppet." He remains jailed while awaiting trial.