A man and two women were also injured in the crash. They were transported in serious to critical condition and remain hospitalized.
"It doesn't happen often, but believe it or not, it does happen," said Lyons Police Commander Brian Kuratko about the accident, which happened in the northbound lanes of 1st Avenue, or Illinois Route 171, near 47th Street.
Police say it appears the driver of a Buick Park Avenue, who was the sole occupant of the vehicle, was traveling southbound in the northbound lanes of 1st Avenue when it collided with a Honda CRV with a family of four inside.
Police say they received a 911 call informing them there was a vehicle driving in the wrong direction on 1st Avenue just minutes before the collision occurred. Although they said they could not confirm that it was one of these two vehicles that was involved in that report, police said they believed that was the case.
All five victims were taken to Loyola University Medical Center where the driver of the Buick -- a man reportedly in his 40s -- along with a 7-year-old boy traveling in the Honda CRV were both pronounced dead.
Detectives investigating the accident say it appears the man believed to be responsible for the accident initially exited Interstate 55, then somehow got turned around.
"It appears he may have gotten off at Harlem Avenue and then did a button-hook and came back toward Archer and 1st Avenue, and if you've been to that area, it's somewhat confusing if you don't know the area," Kuratko said.
Authorities say their preliminary investigation shows that alcohol was not a factor in the collision.
As of Sunday evening, police investigators had not released identities of the victims because of the number of fatalities and injuries. They say they are having difficulty locating the relatives of those in the crash.