It is recognized as the eighth oldest city in Cuba, but its real date of foundation has been obscured over time, and it may be the second Spanish settlement on the island. Historians place the foundation date sometime between 1513 and 1524 by Spanish nobleman Vasco Porcallo de Figueroa, originally founded by him on the 13th of April 1514. Documents reflect that this settlement was only preceded by Baracoa (1511) and (Bayamo)(1512). Considering these facts some believe it was actually founded before Trinidad (1514). Rumor has it that Vasco, in order to avoid tax payments to the crown, maintained the village hidden from the knowledge of the King of Spain as long as he could, but the village grew quickly, and at some point it had to be recognized. Through his wife, the daughter of the Cacique of Sabaneque, Vasco received a huge land grant as a personal fief from Gobernor Diego Velazquez as stipulated by Spanish law, therefore it had no municipal entity to govern the town. Upon Vasco's death in Puerto Principe in 1550 the town obtained its charter.
It was originally called Santa Cruz de la Sabana, Santa Cruz de Vasco Porcallo, Santa Cruz de la Sabana del Cayo and lastly by 1578 San Juan de los Remedios de la Sabana del Cayo. In the 16th, 17th and 18th centuries there was a steady progress defined by land grants, which allowed for a stable population settlement. The economic growth relied on agriculture and cattle raising, eventually becoming one of the major beef suppliers to the Florida colonies.
By 1678 the demarcation between Remedios and Sancti Spiritus was already established. Along with cattle raising the sugar industry was developed and by the end of the 17th and beginning of the 18th century the cultivation of tobacco, coffee and cacao was begun. In 1682, a major dispute arose among the settlers, led by Father Gonzalez de la Cruz, who claimed that satanic forces had taken hold of the place. This led the Spanish Crown to send a Royal Decree dated