The Battle of Cartagena de Indias (Spanish: Sitio de Cartagena de Indias, lit. 'Siege of Cartagena de Indias') took place during the 1739 to 1748 War of Jenkins' Ear between Spain and Great Britain. The result of long-standing commercial tensions, the war was primarily fought in the Caribbean; the British tried to capture key Spanish ports in the region, including Porto Bello and Chagres in Panama, Havana, and Cartagena de Indias in present-day Colombia.

Two previous naval attacks in 1740 had failed and for the third attempt in March 1741, the British had opted for a combined naval and land campaign. The British were initially successful; destroying the chain barrier across the narrow channel of Boca Chica and capturing the Fort San Luis. However a night assault on Fort San Lazaro failed and the British were forced to retreat, having suffered over 9,500–11,500 fatalities, in great part to disease, and considerable material losses. Some units suffered death rates of 80 to 90 percent. The victory demonstrated Spain's ability to defend its position and largely ended military operations in this area. Both countries shifted their focus to the wider European War of the Austrian Succession and hostilities ended with the 1748 Treaty of Aix-la-Chapelle.

The 1713 Treaty of Utrecht, which ended the War of the Spanish Succession, gave British merchants access to Spanish colonies in the Americas, which had hitherto been closed off via mercantilist policies by Spain. This included the Asiento de Negros, a monopoly to supply 5,000 slaves a year to Spanish America, and the Navío de Permiso, permitting two ships a year to transport 500 tons of goods each for sale in Porto Bello or Veracruz. These concessions were assigned to the South Sea Company, which was taken over by the British government after becoming bankrupt in 1720. In the 18th century, European wars were often fought over trade privileges overseas, which the then dominant theory of mercantilism viewed as a finite resource. This meant if British trade increased, Spanish trade had to therefore diminish and so the role of a government was to restrict foreign competition.

As the French previously discovered, high costs meant the majority of the profits which could be gained from the concessions were in smuggling contraband goods, which evaded import duties and deprived the Spanish colonial authorities of much needed revenue. The Spanish Crown was also entitled to 25% of the profits made by the South Sea Company, which were rarely paid, despite their conviction it was immensely profitable. Between 1717 and 1733, only eight merchant ships were sent from Britain to the Americas and the asiento has been described as a "commercial illusion".

These tensions were increased by Spanish resentment at British control of Gibraltar and Menorca, which were confirmed by the Treaty of Utrecht. In the Anglo-Spanish War of 1727 to 1729, Spain laid siege to Gibraltar, while Britain blockaded Portobello; both attempts failed and the two countries made peace in the Treaty of Seville but the underlying issues for the conflict remained unresolved. British merchants wanted easier access to lucrative Spanish markets in the Caribbean Basin, where demand from colonists had created a large black market.

The Spanish were permitted to board British vessels trading with their colonies in the Americas; during a search for illegal goods in 1731, Welshman Robert Jenkins, captain of the Rebecca, claimed a Spanish coast guard officer had severed his ear. The legend this was later exhibited to the House of Commons has no basis in fact but proved useful in persuading the British public to support a war with Spain. Pressure from the British public for a declaration of war arose out of a combination of a political campaign to remove Robert Walpole, the long-serving Prime Minister, and a desire for greater commercial access in Spanish America. On 23 October 1739, Britain declared war on Spain.

The Spanish Caribbean trade had a network of four main ports: Vera Cruz; Cartagena; Porto Bello; and the main port through which all the trade of those three ports came, Havana. On 22 November 1739 the British captured Porto Bello in the Viceroyalty of New Granada. The British attack was part of an attempt to damage the Spanish economy. The poorly defended port was attacked by six British ships of the line under the command of Vice-Admiral Edward Vernon. The relative ease of this capture, although the city was abandoned immediately after the battle, caused jubilation in Britain.

Vernon was given command over one quarter of the Royal Navy, which formed part of a major combined arms amphibious expedition under the overall command of Lord Cathcart. The first goal of the expedition was to capture Havana, the most important of the Spanish ports because it had facilities where ships could be refitted and, by 1740, it had become Spain's largest and most active shipyard. Lord Cathcart died en route and it remained unclear who was in command overall. Cathcart's death resulted in dissension in the British command, preventing the coordination needed for this complex operation.