The collision occurred in extremely foggy conditions at about 8 a.m. Thanksgiving Day on Interstate 10 southwest of Beaumont, a Gulf Coast city about 80 miles east of Houston.
Officials at Acadian Ambulance service told KFDM-TV that at least 51 people have been taken to area hospitals and at least eight are critically hurt.
It wasn't immediately clear how the pileup began, but Jefferson County Sheriff's Office Deputy Rod Carroll said the fog was so thick that deputies didn't immediately realize they were dealing with multiple accidents.
"It is catastrophic," Carroll said. "I've got cars on top of cars."
I-10's eastbound lanes were expected to remain closed for most of Thursday.
Texas Department of Public Safety trooper Stephanie Davis told KFDM that two people in an SUV died after the crash. She said at least 100 cars and trucks were involved in the accident.
Carroll said uninjured drivers tried to help as authorities sorted through the wreckage.
"It's just people helping people," Carroll said. "The foremost thing in this holiday season is how other travelers were helping us when we were overwhelmed, sitting and holding, putting pressure on people that were injured."