The LaPorte County crash took place just after 1:30 a.m. on Interstate 94 at Mile Marker 43, about three miles east of the Michigan City exit.
The drivers have been identified as Juan Nelson Jr., 45, of Portage, Indiana, and Michael Vanderlinden, 38, of Belleville, Michigan, who was driving a Chrysler 300.
When police in Michigan went to VanderLinden's home to notify his family, they found the front door ajar. They went inside and found his 33-year-old wife and two young sons - ages 4 and 7 - stabbed to death in their bedrooms.
Indiana State Police say Vanderlinden's Chrysler got on I-94 traveling eastbound in the westbound lanes. Nelson's vehicle was traveling westbound in the center lane when the two vehicles collided head-on. Vanderlinden traveled the wrong way for a little under a mile before his car struck Nelson's vehicle. The crash impact ignited a fire that engulfed both vehicles.
After firefighters from the LaPorte Fire Department extinguished the flames, both drivers had to be extricated from their vehicles. The LaPorte County coroner pronounced both drivers dead at the scene.
Police in Belleview say they found a weapon in Vanderlinden's house, but decline to say what it is. Nor are they saying whether they believe Vanderlinden committed the murders, and then intentionally caused a crash that took an innocent life.
Police say they were called to Vanderlinden's home late last year after an attempted suicide. Investigators are calling him a person of interest in the deaths of his wife and two children.
The murders of his sons and wife have left neighbors stunned.
"She was sweet. She was always happy go lucky, always smiling. She was one of those neighbors you loved to have," neighbor John Jones said of Vanderlinden's wife.
In Portage, close friends of Juan Nelson's family are struggling with a loss of a man they consider a father figure.
"When I got the message, it hurt. [He was like] my role model," said Torionn Smith, a Nelson family friend, said.
"I didn't believe it at first, I was in shock," said Willie Holloway, Nelson family friend. "It's hard to know it happened to people close to you. You hear it happening to people around the world but you don't believe it will happen to your friends and family."
Nelson was a steel worker at U.S. Steel. He was married and had a son.