Santo Domingo, formerly known as Santo Domingo de Guzmán, is the capital and largest city of the Dominican Republic and the largest metropolitan area in the Caribbean by population. As of 2022,^[update] the city center had a population of 1,029,110 while its metropolitan area, Greater Santo Domingo, had a population of 4,274,651. The city is coterminous with the boundaries of the Distrito Nacional (D.N.), itself bordered on three sides by Santo Domingo Province.

Santo Domingo was founded in 1496 by the Spanish Empire and is the oldest continuously inhabited European settlement in the Americas. It was the first seat of Spanish colonial rule in the New World, the Captaincy General of Santo Domingo. Santo Domingo is the site of the first university, cathedral, castle, monastery, and fortress in the New World. The city's Colonial Zone was declared as a World Heritage Site by UNESCO. Santo Domingo was called Ciudad Trujillo (Spanish pronunciation: [sjuˈðað tɾuˈxiʝo]), from 1936 to 1961, after the Dominican Republic's dictator, Rafael Trujillo, named the capital after himself. Following his assassination, the city resumed its original designation.

Santo Domingo is the cultural, financial, political, commercial and industrial center of the Dominican Republic, with the vast majority of the country's industries being located within the city. Santo Domingo also serves as the chief seaport of the country. The city's harbor at the mouth of the Ozama River accommodates the largest vessels, and the port handles both heavy passenger- and freight traffic.

Prior to the arrival of Christopher Columbus in 1492, the native Taíno people populated the island which they called Kiskeya (mother of all lands) and Ayiti (the land of the high mountains), and which Columbus later named Hispaniola, including the territory of today's Republic of Haiti. At the time, the island's territory consisted of five chiefdoms: Marién, Maguá, Maguana, Jaragua, and Higüey. These were ruled respectively by caciques (chiefs) Guacanagarix, Guarionex, Caonabo, Bohechío, and Cayacoa.

Dating from 1493, when the Spanish settled on the island, and officially from 5 August 1498, Santo Domingo became the oldest European city in the Americas. Bartholomew Columbus founded the settlement and named it La Nueva Isabela, after La Isabela, an earlier settlement in the north named after the Queen of Spain Isabella I. In 1495 it was renamed "Santo Domingo", in honor of Saint Dominic. Santo Domingo came to be known as the "Gateway to the Caribbean" and the chief town in Hispaniola from then on. Expeditions which led to Ponce de León's colonization of Puerto Rico, Diego Velázquez de Cuéllar's colonization of Cuba, Hernán Cortés' conquest of Mexico, and Vasco Núñez de Balboa's sighting of the Pacific Ocean were all launched from Santo Domingo.

In June 1502, Santo Domingo was destroyed by a major hurricane, and the new Governor Nicolás de Ovando had it rebuilt on a different site on the other side of the Ozama River. The original layout of the city and a large portion of its defensive wall can still be appreciated today throughout the Colonial Zone, declared a World Heritage Site by UNESCO.

Diego Columbus, Christopher Columbus's son, arrived in 1509, assuming the powers of Viceroy and admiral. In 1512, Ferdinand established a Real Audiencia with Juan Ortiz de Matienzo, Marcelo de Villalobos, and Lucas Vázquez de Ayllón appointed as judges of appeal. In 1514, Pedro Ibanez de Ibarra arrived with the Laws of Burgos. Diego de Medrano, from Soria, was appointed royal treasurer of Santo Domingo. Rodrigo de Alburquerque was named repartidor de indios and soon named visitadores to enforce the laws.

The first major slave revolt in the Americas occurred in Santo Domingo during 1521, when enslaved Africans led an uprising on Diego Colombus's sugar plantation. In 1586, the privateer Sir Francis Drake captured the city and held it for ransom. A report which reached the English government in May 1586 states that from Santo Domingo he took away 1,200 Englishmen, Frenchmen, Flemings, and "Provincials out of prison, besides 800 of the countrey people". Drake's successful capture signaled the decline of Spain's dominion over Hispaniola, which was accentuated in the early 17th century by Spanish policies that resulted in the depopulation of most of the island outside of the capital. An expedition sent by Oliver Cromwell in 1655 attacked the city of Santo Domingo, but the English force was repulsed by a smaller force of local militias and Santo Domingo suffered only 25 dead. In 1697, the Treaty of Ryswick included the acknowledgement by Spain of France's dominion over the Western third of the island, now Haiti. During the 18th century, privateers from Santo Domingo patrolled the Caribbean, capturing numerous enemy merchantment.