The cities of Trinidad, Camagüey and Sancti Spíritus were founded in the 16th century by a small group of Spaniards led by Diego Velázquez. In the 17th and 18th centuries great landowners, rich from the sugar grown in the surrounding countryside, resided in luxurious mansions in these three cities, but this wealth attracted state-sanctioned pirates. Camagüey (then Puerto Príncipe) was famously raided by the Welsh privateer Henry Morgan in 1666.

In the second half of the 19th century, a period of crisis began with the advent of new technology, for which there was no skilled labour. Slave revolts became increasingly frequent and violent. In the late 19th century the major landowners left the cities and as time went on they gradually ceded their sugar factories to American businessmen, who converted them into one large sugar-producing business. Camagüey turned to raising livestock, while Trinidad engaged in handicrafts and cigar-making. The region remained isolated from the rest of Cuba for a long time, since the railway was not extended to Trinidad until 1919 and the road to Cienfuegos and Sancti Spíritus was only laid out in the 1950s. One result of this isolation, however, is that the historic centres of Trinidad and Sancti Spíritus have preserved their colonial atmosphere.