Cartagena in 1586 was both formidable and vulnerable. The city sat on the coast, protected on its seaward side by natural barriers, with a seawater-filled moat separating it from the mainland and the fortified Bridge of San Francisco providing the only crossing. To the east, swampland and jungle-clad hills formed another barrier. The naval defenses included two well-armed galleys crewed by 300 men under Don Pedro Vique y Manrique, the governor's military advisor, supported by a galleass anchored in the harbor. The total defending force numbered perhaps 570 regulars and militia, augmented by 54 mounted lancers and as many as 300 indigenous allies armed with bows and poisoned arrows. It was a respectable garrison for a colonial city, but Drake's force outnumbered the defenders nearly three to one.

Drake's attack came on the night of February 9. Rather than force the harbor entrance against the Spanish galleys, the English landed troops on the beaches near La Caleta and advanced overland. The Spanish had planted poisoned-tipped stakes along the approaches, a nasty surprise in the darkness, but the English pushed through, absorbing casualties and reforming their lines. When they reached the earthworks covering La Caleta, the Spanish galleys provided supporting fire, but the English broke through and spread into the city. Pockets of Spanish resistance crumbled as Drake's soldiers turned captured Spanish guns against their former owners. Governor Pedro de Bustos and the remaining defenders fled across the Bridge of San Francisco, but even their escape did not end the fighting. Scattered skirmishes continued as the English secured the city block by block.

With Cartagena in his hands, Drake settled in for a negotiation he had no intention of losing. Formal talks began on February 15, when Governor Don Pedro Fernandez was summoned to Drake's quarters along with his lead negotiator, Father Don Juan de Montalvo, deputy governor Don Diego Daca, and Tristan de Oribe Salazar, one of the city's wealthiest merchants. Drake's method was direct: he began burning buildings, section by section, to motivate his counterparts. The final ransom was 107,000 ducats, a sum that reflected both the city's wealth and its residents' desperation to stop the destruction. Drake held Cartagena for more than two months, departing on April 12 with the ransom, considerable additional plunder, and the satisfaction of having humiliated Spain in the heart of its American empire.

Drake's raid left more than ashes. It left fear, and fear built fortifications. In the years following 1586, Spain commissioned the Italian engineer Battista Antonelli to redesign Cartagena's defenses from the ground up. The city that Drake had taken in three days would spend the next century and a half becoming one of the most heavily fortified places in the Western Hemisphere. The massive walls, bastions, and outlying forts that still define Cartagena's Old City today exist because of what happened in February 1586. Drake never returned to Cartagena, but his shadow shaped every stone that was laid after he left. The city that travelers admire today, with its coral-stone ramparts and cannon-studded parapets, is in a real sense the monument to his raid.