It happened at about 4.40pm on Saturday (July 11).
South Yorkshire Police received a number of reports of a woman on the wrong side of the railings over the M18 southbound, between Junction 2 and Junction 1.
Officers believe she fell from Ruddle Lane, a bridge over the motorway, and was then struck by a HGV in the carriageway.
A police spokesperson said: "The 46-year-old was transported to Northern General Hospital where she remains in a critical condition.
"Her family have been informed and are receiving support from specially trained officers."
Police closed the southbound carriageway until late last night while they investigated the incident.
Officers want to hear from any motorists who were travelling on the M18 yesterday afternoon who witnessed the incident or who may have dashcam footage.
Anyone with information should call South Yorkshire Police on 101 quoting incident number 694 of July 11.
Dash cam footage can be emailed to [email protected] quoting the incident number in the subject line.