The crash happened on the southbound carriageway of the motorway between Wolverhampton and Cannock at around 1am.
The collision involved the red MG MG3 car that the woman was driving and a white DAF Trucks lorry.
The woman was pronounced dead at the scene and specialist officers are now supporting her family, Staffordshire Police said.
The driver of the HGV was not injured.
The motorway was closed southbound between Junction 12 for Gailey and Junction 11 for Wolverhampton for around five hours after the crash happened close to Junction 11a.
The road was not fully open again until around 9.30am.
Officers from the Staffordshire and West Midlands Serious Collision Investigation Unit are now appealing for witnesses following the crash.
Anyone who may have seen the vehicles before the collision or has relevant dashcam footage should contact Staffordshire Police on Facebook or Twitter quoting incident number 33 of 23 January, or call 101.