Indiana State Police reported 40 to 60 vehicles, including several semis, are involved in an accident at Interstate 70, just west of State Road 267 near Plainfield.
All lanes are closed in both directions.
Authorities said several people have been transported to Methodist and Hendricks Regional hospitals.
INDOT officials said the lanes are expected to be closed for eight hours.
Fox59 will update the story as more information becomes available.