The M1 was closed in both directions after a lorry crossed the carriageway and collided with other vehicles.
Police said the “multi-vehicle collision” occurred between junctions 14 and 15, near Northampton, shortly before 15:00 BST on Monday.
East Midlands Ambulance Service said two people had been taken to hospital, one by the air ambulance.
Northamptonshire Police said both carriageways were partially reopened by about 18:00.
One patient has been taken to Coventry and Walsgrave Hospital by the air ambulance, while another has been taken to Northampton General Hospital by land ambulance.
Supt Chris Hillery, from Northamptonshire Police, said: “A heavy vehicle has crossed from the northbound to the southbound carriageway colliding with other vehicles coming in the opposite direction.
“You can appreciate whatever the outcome of that, it’s going to be serious.”
Highways England are advising drivers to allow extra journey time or seek alternative routes.
Supt Hillery added: “The officers and responders at the scene are working hard to clear that carriageway so that people can get on about their business.
“But it’s a very serious incident and clearly we have to deal with the people that are impacted by the collision itself as our primary objective.”