He was greatly aided in this goal by his marriage to María de Toledo y Rojas, niece of the 2nd Duke of Alba, who was the cousin of King Ferdinand.

Other loyal Colombistas met him at Santo Domingo - his uncle by marriage, Francisco de Garay, whom he named alguacil mayor, and Bartolomé's criados, Miguel Díaz, Diego Velázquez, and Juan Cerón.

"[2]: 137 In 1511, a royal council declared Hispaniola, Puerto Rico, Jamaica and Cuba under Diego's power "by right of his father."

[2]: 204–210, 213, 215 The first major slave rebellion in the Americas occurred in Santo Domingo on 26 December 1522, when enslaved Jolof laborers working on Diego's sugar plantation started a revolt.

During the rebellion, many formerly enslaved insurgents managed to escape into the mountainous interior of the colony, where they established independent maroon communities amongst the surviving Taíno.

[8][9] After his death, a compromise was reached in 1536 in which his son, Luis Colón de Toledo, was named Admiral of the Indies and renounced all other rights for a perpetual annuity of 10,000 ducats, the island of Jamaica as a fief, an estate of 25 square leagues on the Isthmus of Panama, then called Veragua, and the titles of Duke of Veragua and Marquess of Jamaica.

He initially planned to marry Mencia de Guzman, daughter of the Duke of Medina Sidonia.,[10] but he was forced by King Fernando to marry the king's cousin María de Toledo y Rojas (c. 1490 – May 11, 1549), who secured the transportation and burial of her father-in-law, Christopher Columbus, in Santo Domingo.