Cartagena was founded in 1533 by Pedro de Heredia, in the area where the Caribbean Calamarí people lived, their name meaning 'crab'. This native population was part of a native tribe called the Mocanáes; Spanish accounts describe them as fierce and warlike, and point out that even women fought on a par with men.

A few years after it had been founded, the Spaniards designed a defense plan in which the main strategy was the construction of a walled military fortress to protect the city against the plundering of English, Dutch and French pirates.

Despite the precautions, the city was attacked many times. In 1544 the French pirate Roberto Baal (aka Roberval) forced Governor Pedro de Heredia to flee and to give him gold to avoid being at the mercy of the invaders.
In 1559, the Frenchman Martín Cote also dominated the city.

Another pirate attack was that of Francis Drake, who disembarked at night and took the city at dawn; he forced the inhabitants to take refuge in the neighboring village of Turbaco, burned the houses and destroyed a nave of the Cathedral.

Drake forced the authorities to pay him 107.000 ducats and took some jewelry and 80 artillery   pieces.

And in 1568, the Englishman John Hawkins besieged the city for seven days

In March of 1741 the city was attacked by the troops of the English admiral Edward Vernon, who arrived at Cartagena with an enormous fleet of 186 ships and 23.600 men (the biggest fleet in history until the Disembarkation of Normandy two centuries later) against only 6 ships and 3.600 men. After weeks of intense fighting, the siege was repelled by the Spanish commander, General Blas de Lezo

Cartagena was a major trading port, specially for precious metals.

On 5 February 1610, the Catholic Monarchs established from Spain the Inquisition Holy Office Court in Cartagena de Indias by a Royal Decree issued by King Philip II. The Inquisition Palace, finished in 1770, is still there with its original features of colonial times.

In colonial times, the Spaniards also built a series of constructions and fortresses to defend the city, such as San Sebastián de Pastelillo Fort, in the neighborhood of Manga, and the Castillo de San Felipe de Barajas, a large fortress named in honor of Spain's King Philip IV.