The crash occurred near Highway 20 in Racine County at about 11 a.m. Wednesday.
RAW VIDEO: Fiery scene moments after semi crash, explosion
Police said a semi was traveling southbound when it entered the construction zone. The driver made a lane change, struck a construction barrier, then over-corrected and struck the median wall that separates northbound and southbound lanes before bursting into flame. The impact shoved the median wall into the northbound lanes, police said.
As a result of that median moving, three passenger vehicles collided with the wall and each other, according to the Racine County Sheriff's Office. As a result of that crash, the driver of a semi traveling northbound made a move to avoid the crash, turned into an eastern ditch lane, went off the road and burst into flame.
Police said both semi drivers died. Of the three passenger vehicles, two drivers sustained serious injuries, including burns and broken bones, and were taken to local hospitals for treatment, police said. The third driver walked away from the crash with no injuries.
RAW VIDEO: Traffic camera shows fiery fatal semi crash
Southbound lanes on I-41/I-94 at Ryan Road reopened shortly before 9 p.m. Wednesday. By 6 a.m. Thursday morning, all northbound lanes were back open.
Witnesses said they heard what they described as an explosion and seeing a mushroom cloud of smoke. One of the trucks hung off the side of the expressway.
"I was kind of scared that it was gonna blow up or something, and there was a lot of debris flying everywhere," said Katelyn Planka, witness.
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"There was a lot of crackling and popping at first and as we sat there, maybe three or four minutes later, we heard quite a few bangs as if something was blowing," Planka added.
The Racine County Sheriff's Office said the highway has been under heavy construction and many crashes have occurred. Police are asking commuters to slow down, be aware of their surroundings and remove distractions as they travel through the construction zones.
RAW VIDEO: Semi on fire dangles from overpass
The construction zone where the crash occurred has a modified speed limit of 60 mph.
The Associated Press contributed to this report.