The driver of a green pickup headed northbound on Highway 181 lost control and veered into the southbound lane striking a white pickup truck around 9:30 a.m. Tuesday.
The wreck happened roughly a mile north of FM 81 near Hobson.
The impact killed the driver of the white pickup truck, who officials identified as 27-year-old Lance Bryan of Pleasanton.
An 18-wheeler behind the white pickup also collided with the green truck.
A car swerved to avoid the wreck, but ended up hitting the engine that fell from the green truck.
DPS officials say the driver of the green truck was not wearing a seatbelt and was thrown from the vehicle.
That driver and the driver of the car were airlifted to University Hospital in San Antonio.
The driver of the 18-wheeler was treated at the scene for injuries.
A cleanup crew from San Antonio was called in to clean up liquid that spilled from barrels behind hauled on a trailer behind the green pickup.
The Karnes County Sheriff could not identify the substance but says the liquid was not hazardous.
The lanes of north and southbound 181 reopened around 4:40 p.m. Tuesday.