It happened around midnight at the I-44 and Highway 65 interchange in northeast Springfield.
Police Lt. Greg Wheelen says a sedan, traveling in the westbound lane of I-44 went off the road near the northbound off-ramp, and flipped over.
Police are releasing few details at this point. Wheelen would not confirm a death in the crash, although he told reporters one of the victims had been taken to the hospital and the other remained in the wreckage.
And officers covered up part of the car with a tarp.
Police say they don't yet what caused the crash, but are talking to witnesses. They'll also be investigating whether alcohol was involved.
"(We)..don't know that yet. That will come way down the road after anything we get out of labs and things like that," said Wheelen.
One lane of I-44 was closed for several hours while police investigated.