Crews were called to the scene northbound, between junctions 10 and 11, just before 11.40pm on Saturday.
South Central Ambulance Service said five crews treated victims near Bicester, Oxfordshire.
A spokeswoman said the casualties were taken to hospitals in Oxford and Banbury.
The road was closed in both directions and drivers faced up to three hours of delays.
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Thames Valley Police said: "The northbound carriageway of the M40 between junction 10 and junction 11 is currently closed after a multi-vehicle RTC."
"We would advise motorists to avoid the area at this time while emergency services are at the scene.
"The road is expected to be closed for a number of hours so please find alternative routes."
PlS RT. The northbound carriageway of the M40 between junction ten and junction 11 is currently closed after a multi vehicle RTC.
— Thames Valley Police (@ThamesVP) December 24, 2017
We would advise motorists to avoid the area at this time while emergency services are at the scene. pic.twitter.com/ezYkJI1Gfl
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It is understood the main cause of the delay was due to an overturned vehicle in the road.
A motorist who passed the pile up said he could see about 30 emergency vehicles at the scene.
The motorway is understood to have reopened at 4am.
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Sat in traffic yards away from an horrific accident on the M40. Officer has just told us their are fatalities and many people injured. So very sad.
— Russell Watson (@russellthevoice) December 24, 2017
Following the crash Russell Watson claimed officers at the scene said there were fatalities.
He said: “Sat in traffic yards away from an horrific accident on the M40. Officer has just told us there are fatalities and many people injured. So very sad.”
The crash comes after a lorry caught fire near the same site on Friday, causing severe delays.
It burst into flames close to Junction 9.