Police in Thornton said those killed were in the Chevrolet S-10 pickup.
"All five occupants were pronounced dead at the scene," police spokesman Matt Barnes said.
The rush-hour crash came as a Ford Expedition headed south on a major thoroughfare north of Denver shortly before 6 p.m., Barnes said in a statement.
He said witnesses told police that the SUV was being driven erratically and crossed over the median into the northbound lanes. The vehicle then traveled into an intersection where it hit the rear end of a Mazda sedan, before going airborne and landing on top of the pickup, Barnes said.
An instant later the Ford smashed into a mattress store, slightly injuring one person inside from flying glass and causing extensive damage to the building.
A woman and two juveniles in the SUV and a man who was alone in the Mazda were hospitalized. Barnes said he didn't have any details on their conditions.
KUSA-TV reported that investigators initially believed four people died, but found a fifth body in the truck a few hours after the accident, which occurred shortly before 6 p.m.
"I won't ever forget that sound," Chrissy Pena told The Denver Post, describing the noise of the crash, shattering glass and crunching metal.
I'm still shaking," she said as she and dozens of others stood some 200 feet away from the wreckage.
Barnes said investigators are trying to determine what set off the crash.