Authorities said they had little information on the suspect other than his gender and that they believe he was carrying a gun similar to an AR-15 assault-style weapon.
Police could also not confirm whether the victims were targeted or whether the incident was a case of road rage.
Houston Police Chief Bobby Dobbins said the killings could have been drug-related, as narcotics were found in the targeted car.
"As crazy as things are right now in our society, was this a road rage incident and these guys just happened to have narcotics in the car?" Dobbins told reporters.
The incident unfolded just before 6 p.m. when a car driven by the suspect rammed into another vehicle on Interstate 10 in Houston. The suspect then stepped out of his car and began shooting at the front of the struck vehicle, Dobbins said.
There were two people inside the targeted car.
An unidentified male witness pulled out a pistol and started firing shots at the suspect, Dobbins said. The suspect then fled in his vehicle, along with a male passenger.
Other witnesses tried performing CPR on the two victims before authorities arrived, but to no avail.