In 1514 the Spanish Crown divided Puerto Rico into two administrative districts: the San Germán Party in the west and the San Juan Party in the east, separated by a line from the Camuy River in the north to the Jacaguas River in the south. Over the following centuries San Germán was subdivided into numerous towns—including Aguada, Añasco, Mayagüez, San Sebastián, Ponce, Rincón, Cabo Rojo, Moca, Aguadilla, and others—some of which later merged, split, and eventually became separate municipalities, as in the case of Guánica.

The first rural workforce consisted of enslaved Indigenous people, who died in great numbers, especially from infectious diseases. To replace this labor, Spaniards began bringing enslaved men, women, and children from Africa, making slavery a central institution in the island’s colonial economy

In 1510 the Spanish began assigning groups of Indigenous people to colonists to perform many types of labor. This exploitation helped trigger the Taíno rebellion of 1511, led by Agueybaná the Brave, successor to Agueybaná I, together with Guarionex. The rebels burned the settlement at the Guaurabo River (today the Añasco River) and killed about 80 inhabitants, including Cristóbal de Sotomayor.

According to a popular but undocumented legend, before the uprising the Taínos drowned a Spaniard named Salcedo in the Guaurabo River and watched his body for three days to prove that Europeans were mortal. In March 1511 Ponce de León launched a night attack against several caciques, killing around 200 Indigenous fighters and enslaving many prisoners. Agueybaná was killed by the arquebusier Juan de León at the battle of Yahueca, after which the Taínos retreated. Even so, this first defeat did not end the conflict, which continued through further battles before the Indigenous forces withdrew eastward.

The Coroso tradition (c. 4000 BC–100 BC) was an archaic culture of hunter-gatherers organized in small bands, with recent evidence of some larger settlements. The Saladoid culture (c. 300 BC–600 AD) brought the first farming and pottery-making society from South America to Puerto Rico, with large, well-organized settlements and fine ceramics painted in white, orange, and red on dark red backgrounds.

From c. 600–1200, Ostionoid and Helenoid groups formed the first agricultural societies in Puerto Rico, settling near rivers, founding new ceremonial centers, producing dark ceramics painted in white, orange, or red, and making religious objects linked to cohoba. By c. 1200–1500, Taíno chiefdoms in Borinquen, La Española, and eastern Cuba developed complex leadership structures and highly elaborate ceremonial systems. The Hueca Complex, identified at the Hueca–Sorcé site in Vieques by Luis Chanlatte Baik and Yvonne Narganes Storde, represents a distinct cultural tradition that coexisted with other groups on the island.