The Houston Police Department said the wreck happened at about 2 a.m. on US-59 at Bissonnet Street.
Officers told ABC13 that two people died from their injuries due to the crash.
Although details are limited, investigators said at least one person was ejected from a vehicle.
The police department said investigators are working to learn how many vehicles were involved, what led to the accident, or if anyone else was injured.
The freeway reopened just before 9 a.m. on Sunday.