Two boys and a woman were confirmed dead at the scene of a crash on the M6 motorway in Staffordshire, north of Birmingham, shortly before 11.30am.
One adult woman who was also in the car was taken to hospital for treatment.
Earlier, two people were killed and a third person was left with serious injuries following a crash in Hampshire, southern England
Police were called at 10.05am after a member of the public reported that a car had been involved in a collision near Basingstoke.
A spokesman for the ambulance service said of the M6 crash: "Crews arrived to find a single vehicle that had crashed and overturned. Three children that were travelling in the vehicle suffered serious injuries.
"Unfortunately, despite the best efforts of ambulance crews, nothing could be done to save the two boys and one woman, and they were confirmed dead at the scene.
"Two adult women travelling in the car received emergency treatment at the scene for their injuries and were transferred by land ambulances to University Hospital North Staffordshire on blue (emergency) lights for further treatment."
He added: "All emergency services personnel worked seamlessly together at the scene in exceptionally difficult circumstances.
"Unfortunately, the outcome was not the one that everyone would have hoped for."
Two air ambulances and three ambulances attended the scene, which closed the motorway in both directions for several hours.
A Highways Agency spokesman said checks of CCTV cameras near the scene of the crash soon afterwards showed that the weather conditions were "dry and fine at the time".
The wreckage of the car was covered with a blue tarpaulin before being removed from the carriageway. The motorway was reopened in both directions by 4pm.
In the earlier incident, a couple were killed after they had been taken for a drive by their son shortly after 10am.
The husband and wife died when the silver-coloured car veered off the road near a bend and crashed into trees before flipping onto its side at Riseley, Berkshire, on the border with Hampshire.
The driver, a young man aged in his 20s who is believed to be the dead couple's son, suffered serious chest injuries and was taken to hospital.
Earlier, a man was injured after his vehicle had split into at least three pieces following a collision between junctions 5 and 6, near Wolverhampton in the English midlands, on the M6 Toll road at around 3.35am.
The man, in his mid-20s, suffered multiple minor injuries and was taken to hospital for treatment.
A spokesman for the ambulance service said: "Considering the damage to the vehicle, the man was extremely fortunate not to have suffered more serious or even fatal injuries."