In 1511 he accompanied Diego Velasquez, who was sent out by Diego Columbus to subdue and colonize Cuba. Later he held the office of alcalde of Santiago in the new colony, and meanwhile he married Catalina Juarez, a Spanish lady who had come over in the suite of Maria de Toledo, the vice-queen. After his marriage he employed himself and his Indians in getting gold. "How many of them died in extracting this gold for him, God will have kept a better account than I have," says Las Casas. Grijalva, a lieutenant of Velasquez, had just discovered Mexico, but had made no attempt at its settlement.

This displeased the governor, and Cortes was given the command of a new expedition about to start for the conquest of the newly discovered province. At the last moment, Velasquez appears to have regretted the appointment, possibly fearing that Cortes would carry off all the glory as well as the profit of the enterprise, and endeavored to recall the expedition; but Cortes hastened his preparations, and on the 18th of November, 1518, left Santiago with 10 vessels, 550 Spaniards, nearly 300 Indians, a few Negroes, 10 brass guns, a dozen horses, and some falconets. Collecting stores on his way, he arrived at Trinidad, and later at Havana, at both of which places he found orders from Velasquez depriving him of his command, but in neither place could they be enforced, so. after writing a letter of remonstrance to the governor, he sailed, on 10 Feb., 1519, for the island of Cozumel, on the coast of Yucatan. On 4 March he first landed on the shores of Mexico, in the province of Tabasco, advancing slowly along the gulf. Sometimes taking measures to conciliate the aatires and sometimes spreading terror by arms, he finally reached and took possession of the city of Tabasco.