Drake had a cannonball flown directly through his legs, but was uninjured.

Drake worked at sea until he was in his mid-fifties. After a catastrophic campaign against Spanish America, he failed to take control of the port of Las Palmas in 1595. He then attempted to take control of San Juan de Puerto Rico but was defeated at the Battle of San Juan. The following feat of Drake is a step closer to full-scale conflict between England and Spain. This was the West Indies attack in 1585–1586, which demonstrated how unprepared the Spaniards were for defense on their Atlantic shores as they were on their Pacific ones. In this attack, Drake had a cannonball fly directly through his legs but was uninjured. In particular, he was shot by Spanish gunners with a cannonball from El Morro Castle through the cabin of the flagship Drake in the harbor battle at Palma about Drake's raid into Cartagena de Indias, West Indies, and fortunately, he survived.

However, Drake failed in his effort to launch a ground invasion to seize the lucrative port of Panama. A few weeks later, on January 28, 1596, when anchored off the coast of Portobelo, where other Spanish treasure ships sought safety, he passed away (at the age of roughly 56) from dysentery, a condition prevalent in the tropics at the time. The British fleet's withdrawal was stopped after his death.