A tractor-trailer was headed south on I-55 about 4:50 p.m. when it apparently ran off the west side of the roadway just south of mile marker 97.2, crashed through a guardrail and plunged down a steep embankment into a wooded area.
Cape Girardeau police arrived to find the vehicle engulfed in flames, public information officer Darin Hickey said in a news release.
The driver, whose name had not been released Wednesday evening, was unable to escape the vehicle, Hickey said.
Cape Girardeau County Coroner John Clifton declared the driver dead at the scene.
As he waited for emergency workers to pull the vehicle back onto the roadway and remove the victim's body, Clifton said he was "reasonably certain" the driver was the only person killed in the crash.
Clifton said he did not know the gender of the driver.
At least a dozen emergency vehicles were at the scene, including a Fruitland fire department tanker and a large wrecker from Carnell's Garage.
I-55 traffic was diverted onto Kingshighway immediately after the crash.
Officers allowed some traffic to pass before closing the lane again to allow the wrecker to pull out part of the damaged guardrail.
The lane closed and reopened several times as workers maneuvered the wrecker into position and prepared to move the semi.
Both lanes were reopened by 10 p.m.
The semi appeared to have been towing a tractor-trailer with a "flammable" placard on it.
It was not clear whether flammable materials were on the trailer during the crash, but a chemical odor drifted through the air near the site. Several trees near the vehicle were charred.
Twisted and broken saplings revealed the path the vehicle took into the wooded area, and Missouri Department of Transportation workers used a chain saw to remove a larger tree that was leaning over the shoulder of the road near the crash site.
More than three hours after the accident, intermittent lane closures continued on southbound I-55 as emergency responders worked to clear the scene.
Interstate 55, Cape Girardeau, Mo.