"There have been four deaths of Spanish nationality, nine Spanish wounded, the Indian driver died also," the ministry said in a statement, adding that consular officials were working with Indian authorities.
The Press Trust of India news agency reported that a minibus carrying 10 Spanish nationals collided with a container truck in Andhra Pradesh state, killing four of the Spanish visitors, including two women, and the local driver of the bus.
The Spaniards were on a visit to see development work undertaken in the area by a trust that is run by a group from Spain, PTI said.
Of the six injured, one person was in a critical condition, PTI said.
India has some of the world's deadliest roads with more than 150,000 fatalities annually due to poor roads, badly maintained vehicles and reckless driving.
In April a bus swerved off a mountain road in northern India, killing 44 people.