Two air ambulances were scrambled to an accident which closed the M6 between Carnforth and Kirkby Lonsdale.
A Mercedes E350 car left the motorway slipway on the northbound carriageway at junction 36 before falling down an embankment.
The driver - a 51-year-old woman from Wiltshire - suffered minor injuries after the incident, which happened at around 1.20pm.
Her front seat passenger - a man aged 50 - was flown to hospital with serious injuries.
Emergency services including paramedics and firefighters were at the scene for around two hours.
The motorway was closed in both directions to allow the helicopters to land and for casualties to be dealt with.
At around 3.15pm the northbound lanes were re-opened, followed by the southbound side shortly after.
Police thanked motorists for their patience.