The incident happened at about 1.45pm on the N17, on the Milltown side of Tuam.
It is understood a car struck a father and his two children as he was walking them on the hard shoulder
Gardaí say the two children were both girls, one aged two-years-old and other aged two months.
They were taken by ambulance to University College Hospital in Galway, where they were pronounced dead.
The male driver and the children's father were also taken to University Hospital Galway. Their injuries are not believed to be life-threatening.
The N17 at Dunmore is closed, pending the completion of an examination of the scene, and diversions are in place.
Gardaí say the road is closed and diversions are in place. They have asked for witnesses to the crash to contact Tuam Garda Station on 093 70840.
Meanwhile in Co Cork, a motorcyclist has died in a road crash near Dripsey.
The man, who is believed to be in his 30s, died after his motorbike collided with a car close to the Inniscarra dam at around 2.15pm.
The road between Dripsey and Cannon's Cross is closed for a technical examination and diversions are in place.
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