Cika wannan jumlar: Tun daga shekara ta 1493, lokacin da Mutanen Espanya suka zauna a tsibirin, kuma a hukumance daga 5 ga Agusta, 1498, Santo Domingo ya zama birni mafi tsufa na Turai a Amurka. Bartholomew Columbus ya kafa wurin kuma ya kira shi La Nueva Isabela, bayan wani wuri na farko a arewa da ake kira bayan Sarauniya na Spain Isabella I. A cikin 1495 an sake masa suna "Santo Domingo", don girmama Saint Dominic. An san Santo Domingo da "Gateway to the Caribbean" kuma babban birni a Hispaniola daga lokacin. Tafiya da ta haifar da mulkin mallaka na Ponce de León na Puerto Rico, Diego Velázquez de Cuéllar na mulkin mallaka na Cuba, Hernando Cortes '
mamayar Mexico, da Vasco Núñez de Balboa na ganin Tekun Pacific duk an kaddamar da su daga Santo Domingo.