He was the son of Hercule, Lord of Monaco (24 September 1562 - 21 November 1604) and Maria Landi. His father was murdered, when he was six, and he succeeded under the regency of his uncle, Frederico Landi, prince of Val di Taro. Landi was a loyal ally and friend of Spain and allowed the country to be occupied by Spanish troops in 1605. The inhabitants of Monaco were prohibited to carry arms and the Prince and his two sisters were moved to Milan. The Council of Monaco tried to limit Spanish power but the occupation lasted until 1614, and a strong Spanish influence remained until 1633, when it recognized Honoré as a sovereign prince.
From adulthood, Honoré started to criticize Spain and turned to France for support. Louis XIII gave him the support he needed and this resulted in the Treaty of Péronne. This ended Spanish rule and put Monaco under French protection, recognizing and guaranteeing Monegasque sovereignty. As a consequence Honoré lost his Spanish and Italian possessions, but was compensated by King Louis XIII of France with the marquisate Les Baux and the title of Duke of Valentinois.
After Hercules was killed in battle, his 9 year old son Louis became Honoré's heir.