The municipality extends over 1,023.8 square kilometers (395 sq mi), and contains the communities of El Caney, Guilera, Antonio Maceo, Bravo, Castillo Duany, Leyte Vidal and Moncada.
Santiago de Cuba was founded by Spanish conquistador Diego Velázquez de Cuéllar on June 28, 1514. In 1516 the settlement was destroyed by fire, and was immediately rebuilt. This was the starting point of the expeditions led by Juan de Grijalba and Hernán Cortés to the coasts of Mexico in 1518, and in 1538 by Hernando de Soto's expedition to Florida. The first cathedral was built in the city in 1528. From 1522 until 1589 Santiago was the capital of the Spanish colony of Cuba.
The city was plundered by French forces in 1553, and by British forces under Christopher Myngs in 1662.
On June 12, 1766, the city was almost destroyed by an earthquake.
The city experienced an influx of French immigrants in the late 18th century and early 19th century, many coming from Haiti after the Haitian slave revolt of 1791. This added to the city's eclectic cultural mix, already rich with Spanish and African culture.
It was also the location where Spanish troops faced their main defeat at San Juan Hill on July 1, 1898, during the Spanish-American War. Spain later surrendered to the United States after the destruction of its Atlantic fleet just outside Santiago's harbor.
Cuban poet, writer, and national hero, José Martí, is buried in Cementerio Santa Efigenia.
Santiago was also the home of the revolutionary hero, Frank Pais. On July 26, 1953, the Cuban Revolution began with an ill-prepared armed attack on the Moncada Barracks by small contingent of rebels led by Fidel Castro. Shortly after this disastrous incident, País began talking with students and young working people informally, drawing around him what became an extremely effective urban revolutionary alliance. This developed into highly organized cells coordinating a large scale urban resistance that became instrumental in the success of the Cuban Revolution.
País' group prepared carefully, accruing weapons, collecting money, collecting medical supplies. They published a cheap newsletter that reported news that criticized the government, attempting to counter Batista's censorship.
In the summer of 1955, País’ organization merged with Castro's July 26 Movement. País became the leader of the new organization in Oriente province.
On 1 January 1959, Fidel Castro proclaimed the victory of the Cuban Revolution from a balcony on Santiago de Cuba's city hall.
Until a rearrangement of province boundaries in 1976, Santiago de Cuba was the capital of Cuba's Oriente Province, which included the present day provinces of Holguín, Las Tunas, Guantánamo, Granma and Santiago de Cuba.
The local citadel of San Pedro de la Roca is inscribed on the UNESCO World Heritage List as "the most complete, best-preserved example of Spanish-American military architecture, based on Italian and Renaissance design principles".
The Baconao Park was inscribed on the UNESCO World Heritage Biosphere Reserve List in 1987.
In 2004, the municipality of Santiago de Cuba had a population of 494,337. With a total area of 1,024 km² (395.4 sq mi), it has a population density of 482.8/km² (1,250.4/sq mi).