He was one of the leaders of the commune uprising of Castile. He was captain of Toledo, his hometown, which he called the uprising against the Government of the new King Carlos I. After that, other stocks such as Segovia, Juan Bravo to the front, and Salamanca, with Francisco Maldonado to the head, followed the example of that, helping them Padilla to reject the realists in meetings that they had. Then convened a meeting in Ávila which attended by representatives of all the rebel towns. Meanwhile, Queen Juana was confined in Tordesillas, ignorant situation that crossed the country, so Padilla headed toward that city with a detachment, put her abreast of the situation and, convinced that's what this said, confirmed him the title of captain general and asked him to return to Tordesillas the Junta of Ávila. Most of the important towns of Spain followed the movement, and the Regents were lost.Only when the viceroy of Navarre provided them with troops and the King of Portugal money, they managed to gather an army to fight the comuneros, troops who were under the command of the count of Haro. He then started the fight, where lack of capacity of management and organizational intelligence, coupled with the betrayal of Pedro Girón, who sent the popular army, and Pedro Lasso, who defended Valladolid, resulted in the loss of that cause. The troops of Padilla were achieved by the of the count of Haro near Villalar, where the unequal battle unfolded on April 23, 1521. Padilla was defeated and taken prisoner, after which he was led to the population which was beheaded the following day, despite letters of request of Amnesty who wrote both the city of Toledo as his wife, María Pacheco. With him died Juan Bravo, Francisco and Pedro Maldonado, and other supporters of the comuneros cause.
See Guerra of the communities.