The death toll from a high-speed train collision in southern Spain rose to 40 on Monday as the government vowed a full investigation into its causes.

The crash late on Sunday is Spain's deadliest train accident since 2013, when 80 people died after a train veered off a curved section of track outside the northwestern city of Santiago de Compostela.

The latest happened when a train operated by rail company Iryo travelling from Malaga to Madrid derailed near Adamuz in Andalusia.

It crossed onto the other track, where it crashed into an oncoming train, which also derailed.

There are currently 40 confirmed deaths from the accident, the head of the regional government of Andalucia, Juan Manuel Moreno, told a news conference, raising the toll from 39.

It will take 24-48 hours "to know with certainty how many deaths have resulted from this terrible accident," he added.

Heavy machinery was deployed earlier on Monday to lift the most severely damaged train carriages and give rescuers better access to the site of the disaster.

Over 120 people were injured, with 41 still in hospitals in the nearby city of Cordoba, Moreno said.

Relatives and friends of missing passengers have turned to social media, posting photos in an effort to find them.

"This is a day of sorrow for all of Spain, for our entire country," Prime Minister Pedro Sanchez told reporters during a visit to Adamuz as he declared three days of mourning.

"We will uncover the answer, and once the cause of this tragedy is determined, we will present it with absolute transparency."

Aerial footage of the crash site from Spain's Guardia Civil police force showed the two trains far apart, as rescuers in high-visibility neon vests worked nearby.

Unlike the 2013 accident, the derailment occurred on a straight section of track, and the trains were travelling within the speed limit, officials said.

Transport Minister Oscar Puente said the first train to derail was "practically new" and the section of the track where the disaster happened had been recently renovated, making the accident "extremely strange."

Train operator Iryo said the locomotive was built in 2022 and last inspected just three days before the accident. It said it "veered onto the adjacent track for still unknown reasons."

The company said around 300 people were on board its service from the Andalusian city of Malaga to the capital, Madrid.

Renfe, the operator of the second train travelling to the southern city of Huelva, said it was carrying 184 passengers.

Human error has "been practically ruled out," Renfe president Alvaro Fernandez Heredia told Spanish public radio RNE.

Heredia also ruled out speeding as a cause of the accident. He said both trains were travelling just over 200 kilometres per hour, below the 250 kilometres per hour limit for that section of track.

"It must be related to Iryo's rolling stock or an infrastructure issue," he added.

Spain has Europe's largest high-speed rail network, with more than 3,000 kilometres of dedicated tracks connecting major cities including Madrid, Barcelona, Seville, Valencia and Malaga. (AFP)