His titles were divided amongst his son Manuel and his nephew Pedro de Alcántara Téllez-Girón (1810–1844), who became 14th Duke of the Infantado.

A revolt in March 1808 resulted in the abdication of the king, the sacking of his manipulative chief minister Godoy and the ascent of Ferdinand VII to the Spanish throne, with the Duke of Infantado at his side.

The only major Spanish figure that spoke in opposition was the Duke of Infantado, who "had opposed to the utmost any recognition of the foreign monarch".

He was highly regarded by the British plenipotentiary, John Hookham Frere, who was accustomed to late and inaccurate intelligence from his allies: "Had Sir John Moore been so fortunate as to find so candid a correspondent as the Duke of Infantado, a person who would describe things as they were, there is no doubt that the events and conclusion of the campaign would have been very different",[4] referring to Moore's retreat to Corunna.

In 1811, the Spanish parliament, the Cortes, nominated him as President of the Council of Spain and sent him on a secret mission to the Prince Regent in London.

He returned in 1812, and although he was proposed by Wellington as head of the 4th Army, under British control, his enemies at the Spanish court decreed otherwise, and he had to be content with leading his own regiment.