Newtonian natural philosophy first circulated in America–in the first half of the eighteenth century–during the colonial activities associated to the scientific expeditions to Perú and Quito. However, it was not until the Bourbon Reforms in the way supported by the reign of Carlos III, in the second half of the eighteenth century, that the educational system of the Spanish colonies was seriously considered as needing a deep reform for the economic and social improvement of the Empire. Such an educational system of the New Granada was ruled by the Dominican order whose curricula were shaped by the traditional Aristotelian-Scholastic ideas and it permeated the intellectual and social activities of the colony. José Celestino Mutis y Bossio (1732-1808) is well known for his leading role in the Royal Botanical Expedition. He was a Spanish priest that arrived at the Audience of Santafé de Bogotá in 1761 having finished his medical education in Cadiz to become the physician of the new Viceroy Pedro Messía de la Cerda. However, historians have seriously overlooked his defence of the Newtonian natural philosophy, and his arguments in favour of the usefulness of mathematics for the Viceroyalty, in contrast to the Scholastic thought highly dominant within the social and academic circles of the colony. Mutis' defence of the 'new philosophy' included the first translation into Spanish of Newton’s Philosophiae naturalis principia mathematica (circa 1770), the creation of the first Chair of Mathematics in the Colegio Mayor de Nuestra Señora del Rosario (1762) along the lines of Newtonian natural philosophy, and the foundation of the first astronomical observatory in America (1802). It is in this context that this paper aims to expose how Mutis' arguments in defence of Newton's natural philosophy were shaped by the colonial interests of the Bourbon reforms and particularly by the political theology there outlined against the traditional and dominant ideas and political structure of the Dominican Order, which even appealed to the Holy Inquisition against Mutis' reformist ideas.