The incident occurred at approximately 7.40pm on Thursday night.
Three cars were involved in the collision on the M6 at Poolboy, Ballinasloe.
Four people were pronounced dead at the scene and removed to Portiuncula Hospital. Post mortem examinations are set to be carried out.
The M6 is now closed in both directions between Junction 14 and 15 as Forensic Collision Investigators examine the scene. Local diversions have been put in place for the duration of the closures.
Gardaí are asking any witnesses to come forward. They are particularly interested in any motorists who may have captured footage, such as dash-cam recordings, of the incident.
Anyone with relevant information should contact Ballinasloe Garda Station on 090 9631890, the Garda Confidential Line on 1800 666 111, or any Garda Station.
