More than 50 people were taken to hospital and at least eight were critically hurt, local media report.
It happened at Interstate 10 near Beaumont, about 80 miles (130km) east of Houston, on Thanksgiving morning.
Rescuers scrambled to pull survivors from miles of wreckage, which left mangled lorries on top of each other.
'Catastrophic' A man and woman died after their sports utility vehicle was crushed by a tractor trailer, reports KFDM-TV (external - login to view).
Emergency services did not initially realise the scale of the carnage because of the dense fog.
Jefferson County Sheriff's Office Deputy Rod Carroll said: "It is catastrophic. I've got cars on top of cars."
The motorway's eastbound lanes were expected to remain closed for most of Thursday.
BBC News - Two killed in 100-vehicle pile-up in US (external - login to view)