At the end of September 1805, Villeneuve had received orders to leave Cádiz and land troops at Naples to support the French campaign in southern Italy. On October 19–20 his fleet slipped out of Cádiz, hoping to get into the Mediterranean Sea without giving battle. Nelson caught him off Cape Trafalgar on October 21.

Villeneuve ordered his fleet to form a single line heading north, and Nelson ordered his fleet to form two squadrons and attack Villeneuve's line from the west, at right angles. By noon the larger squadron, led by Admiral Cuthbert Collingwood in the Royal Sovereign, had engaged the rear (south) 16 ships of the French-Spanish line. At 11:50 AM Nelson, in the Victory, signaled his famous message: “England expects that every man will do his duty.” Then his squadron, with 12 ships, attacked the van and centre of Villeneuve's line, which included Villeneuve in the Bucentaure. The majority of Nelson's squadron broke through and shattered Villeneuve's lines in the pell-mell battle. Six of the leading French and Spanish ships, under Admiral Pierre Dumanoir, were ignored in the first attack and about 3:30 PM were able to turn about to aid those behind. But Dumanoir's weak counterattack failed and was driven off. Collingwood completed the destruction of the rear, and the battle ended about 5:00 PM. Villeneuve himself was captured, and his fleet lost 19 or 20 ships—which were surrendered to the British—and 14,000 men, of whom half were prisoners of war. Nelson was mortally wounded by a sniper, but when he died at 4:30 PM he was certain of his complete victory. About 1,500 British seamen were killed or wounded, but no British ships were lost. Trafalgar shattered forever Napoleon's plans to invade England.