West Midlands Ambulance Service (WMAS) said the three children - two boys and one girl - were travelling in a vehicle on the M6 that had crashed and overturned.
They suffered serious injuries and could not be saved, a spokesman said.
Two women who were also in the car were treated at the scene before being taken to hospital.
The accident happened at around 11.30am on the northbound carriageway between junctions 14, near Stafford, and 15, near Stoke-on-Trent.
The motorway was closed in both directions. A spokesman for the Highways Agency said diversions were in place and delays to traffic were around 30 minutes.
Northbound traffic was being diverted leaving at junction 14 and rejoining at junction 15, following the signed diversion via the A34 and A500.
Southbound traffic was being diverted, leaving at junction 15 and rejoining at junction 14, following the diversion via the A500 and A34.