The first crash happened just after 4:30 a.m. at mile marker 155, about 1.5 miles ahead of the Buckhorn Road exit, and involved five vehicles.
Multiple injuries were reported, but the extent of the injuries have not been released.
The incident caused two of the four lanes of the highway to be closed near the Tanger Outlet in Mebane.
About an hour later, two vehicles crashed in the same area, causing authorities to close down all of the eastbound lanes of I-40 and northbound lanes of I-85.
All four lanes of the interstate reopened around 6 a.m.