The League City Police Department said the wreck happened just before 3:30 a.m. near FM 646.
Authorities closed the southbound lanes for at least six hours as they inspected the roadway for any damage from the fire.
Police said multiple people called the department, reporting a major head-on collision and that one car was on fire.
First responders found one woman alone in one of the vehicles and took her to the hospital in critical condition.
Officers said a man and another woman were inside the second vehicle and were pronounced dead at the scene.
Investigators didn't specify which person was the wrong-way driver, and it's unclear which car was engulfed in flames.
Anyone who might have witnessed this incident or who might have further information is encouraged to contact the League City Police Department at 281-332-2566.