Published: 05 Nov 2016 14:11 GMT+01:00
Mikel Irastorza, 41, was found in a home in the French town of Ascain, in the Pyrenees region bordering Spain, the interior ministry said in a statement.
The couple housing Irastorza -- a 59-year-old Basque exile and his 56-year-old wife -- were also taken into custody, French sources said.
Anti-terrorism prosecutors in Paris authorised the arrests and the three are due to appear before a judge in the French capital. French authorities opened a preliminary investigation into alleged criminal association with a terrorist organisation.
The Spanish statement said the raid, led by French security forces working with Spanish police, was aimed at the "leadership structure of ETA".
Irastorza was described by the ministry as "currently the most senior leader of the terrorist group ETA still at large". Spain said other arrests could follow.
Founded in 1959, ETA waged a violent decades-long campaign for an independent Basque homeland in northern Spain and southwestern France, and is blamed for the deaths of more than 800 people.
It declared a ceasefire in October 2011 but has refused to give up its weapons, and is seeking to negotiate its dissolution in exchange for amnesties or improved prison conditions for the roughly 350 ETA members held in both countries.
Spain's new Interior Minister Juan Ignacio Zoido, who was only appointed on Thursday, welcomed the arrest.