Warned of the impending St. Bartholomew's Day massacre he retired hastily to Dauphiné, where he secretly equipped and drilled a determined body of Huguenots, and in 1575, after the execution of Charles du Puy de Montbrun in Grenoble, became the acknowledged leader of the Huguenot resistance in the district with the title of commandant general, confirmed in 1577 by Marshal Doraville, by Henry II, Prince of Condé in 1580, and by Henry of Navarre in 1582.

In 1590 he overcame the resistance of Grenoble, and was now able to threaten the leaguers and to support the governor of Provence against the raids of Charles Emmanuel I, Duke of Savoy.

[citation needed] After his defeat of the Spanish allies of Savoy at Salbertrand in June 1593 there was a truce, during which Lesdiguières was occupied in maintaining the royal authority against Épernon in Provence.

Nevertheless, he made him a marshal of France in 1609, and ensured the succession to the lieutenant-generalship of Dauphiné, vested in Lesdiguières since 1597, to his son-in-law Charles de Crequy.

Sincerely devoted to the throne, Lesdiguières took no part in the intrigues which disturbed the minority of Louis XIII, and he moderated the political claims made by his co-religionists under the terms of the Edict of Nantes.

[citation needed] Lesdiguières had the qualities of a great general, but circumstances limited him to the mountain warfare of Dauphiné, Provence and Savoy.