Rubuta ci gaba don wannan sakin layi - Tun daga 1493, lokacin da Mutanen Espanya suka zauna a tsibirin, kuma a hukumance daga ranar 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 mulkin mallaka na Cuba, Hernando Cortes na cin nasarar Mexico
, da kuma ganin Vasco Núñez de Balboa na Tekun Fasifik duk an kaddamar da su daga Santo Domingo.