Lucien became Lord of Monaco on 11 October 1505, having murdered his predecessor and brother, Jean II, and held that sovereignty until his death. He was the fourth son of Lambert Grimaldi and Claudine Grimaldi.
A year after Lucien's reign began, Genoa broke free of France, and many of its people fled to Monaco for refuge. In December 1506, 14,000 Genoese troops besieged Monaco and its castle. The blockade lasted for five months, until Lucien was able to rout the Genoese in March 1507. Monaco, and by extension Lucien, was now in a tight spot, being subjects of France but caught in a diplomatic tight spot between France and Spain, trying to preserve its fragile independence.
In 1515, Lucien bought the feudal rights over the city of Mentone, retained by the family of Anne de Lascaris, Countess of Villars, thus bringing the city, as a whole, under Monaco's sovereignty until the French Revolution.
On 22 August 1523, Lucien was assassinated by his nephew, Bartholomew Doria of Dolceaqua, son of Lucien's sister Francoise Doria, at the Prince's Palace of Monaco. He was succeeded by his youngest son, Honoré.