The battle of Cartagena pitted a British invasion force of at least 26,400, 12,000 of which were infantry, in numerous ships and veesels against a force of 3,000 Spanish and colonial regulars, an unspecified number of sailors and armed townsmen and 600 Indian archers, perhaps up to 6,000 combatants, fighting from six frigates and massive fortifications —nder the command of the Viceroy Sebastián de Eslava, Don Melchor de Navarrete, Don Carlos Des Naux, and Don Blas de Lezo.

The British expedition arrived off Cartagena on March 4 and after a couple of weeks bombardment the initial attack made by land and sea at Boca Chica, the Little Mouth, on April 5. This channel ran between two narrow peninsulas and was defended on one side by the fort of St. Louis, Boca Chica Castle, with four bastions having some 80 cannons, on the other side of the channel an earthwork battery of 15 cannon all supported by redoubts. A boom stretched from the island of La Bomba to the southern peninsula on which was Fort St. Joseph with 21 cannon. Also supporting the entrance were the 6 Spanish line ships. The British army forces on land established a battery and made a breach in the main fort while part of the fleet assisted and another part of the fleet engaged the Spanish ships which, ultimately, Lezos tried to scuttle and set on fire. Two Spanish ships partially blocked the channel and one was captured by the British before it could sink. An advance was made on the breach, however the Spanish had already retired to fortifications in the inner harbor on the March 24. The landing force re-embarked and the harbor then entered. The next council of war decided to attempt to isolate Cartagena from the land side by an assault of Fort St. Lazar. The assault failed with a loss of 600 casualties.
Blas de Lezo by unknown painter

Don Blas de Lezo's plan was that, given the overwhelming force against him, he hoped to conduct a fighting withdrawal and delay the British long enough until the start of the rainy season at the end of April. The tropical downpours would effectively end campaigning for another 2 months. Also, the longer the enemy had to remain mostly at sea and in the open the more likely it would become that insufficient supply, discomfort and especially disease would become his allies and the deadly enemies of the British. De Lezo was aided in this by the contempt that Vernon and Wentworth had for each other which prevented any further cooperation after the initial landing. Wentworth was goaded by Vernon into an ill-considered, badly planned assault on Cartagena which Vernon refused to support with the fleet making specious excuses about the depth of the harbor.

An experienced, wily and tenacious Spanish Naval commander, de Lezo, whose previous career was as daring and spectacular as any naval officer of his day, made use of every advantage, strategy and tactic available to him. Cartagena's defensive fortifications had been repaired and improved over the past year. Although De Lezo was pressed to the limit, his plan bore the hoped for fruit. The rains came and the British had to board their ships, where close quarters made disease even more deadly, and by April 25, Vernon resolved to retreat to Jamaica and by mid-May they were gone.

The battle lasted 67 days and ended with the British fleet withdrawing in defeat, with 18,000 killed and wounded , half of them to disease. 50 ships were sunk or abandoned for lack of crew.