Sancti Spíritus was one of the first seven towns founded by Spanish conqueror Diego Velázquez in the island. After the founding of Bayamo, the second town, he decided to build that of La Santísima Trinidad and another, which he would call Espíritu Santo (Holy Ghost), around 1514, becoming a new populated area in the site known as Cayo de la Iglesia.
There are different versions as to the causes for transferring the town to another territory, but the fact is that, in 1522, it became the town of Yayabo once it was moved to the surroundings of a river bearing the same name, exactly where it is nowadays.
As part of the central region, the economy of the province collapsed in the 19th century when western landowners and industrials managed to modernize the processes for obtaining sugar thanks to the introduction of the steam engine and the advantages of railroad transportation. Although Sancti Spíritus and Trinidad had good sugar mills, they could not compete with those of the west.
In 1868, the Ten-Year War started and at the beginning of 1875 the independence forces, coming from the province of Oriente, started the invasion of Las Villas in order to take war westward. Formed by about 1000 men, the force was led by General Máximo Gómez. On January 6, 1875, they entered the territory of Las Villas and several battles took place in the territories of Sancti Spíritus, Manicaragua, Cienfuegos, and others. The campaign could not be taken to a happy ending this time, owing to division, regionalism as well as indiscipline of the troops which cause them to disperse. However, patriots like Serafín Sánchez, Leocadio Bonachea, and Carlos Roloff engaged in a guerrilla fight against the Spanish columns.
In the war of 1895, in the heroic quest of the east-west invasion, Sancti Spíritus Fourth Corps, commanded by General Serafín Sánchez, joined the invasion forces and proved the same courage and discipline of the previous war. From their arrival on December 3, the invasion forces counted on the heroism of the insurrectionists who struggled courageously in Sancti Spíritus and Trinidad.
In the liberation war that ended with the triumph of the revolution on January 1st, 1959, the province of Sancti Spíritus played an important role: they gave an extraordinary support to the invasion troops commanded by Ernesto Che Guevara, which allowed them to take over the cities of Cabaiguán and Sancti Spíritus and other territories, which opposed no resistance, on December 21. All those actions paved the way for attaining the main objective of the invasion forces: the takeover of Santa Clara.