In 1820, American Protestant missionaries entered into the Western Anatolian lands and communities of the Ottoman Empire. Within thirty years, they succeeded both in establishing Protestant missionary communities throughout some of the empire’s territories and in acquiring official recognition from the Sultan. Apart from their direct propagation of Protestantism, missionaries also concentrated their energies on projects that might be viewed, on the one hand, as rendering assistance to the local populations but that, on the other hand, as both attracting a wider demographic and legitimizing their presence and allied spiritual-political missions. Such projects ranged from acts of charity and relief, to education, schooling, and publishing, and to fostering public health and delivering medical services. Locally establishing themselves in this manner vis-à-vis the empire’s populace, American missionaries positioned themselves to be far more than just spiritual caregivers. While past studies of missionaries in the Middle East examined their socio-political consequences, educational agendas, and religious endeavors, few addressed the profound impacts that they had in terms of public health and medicine. This is surprising in that missionaries established themselves in positions of socio-psychological superiority over indigenous populations not only in terms spiritual, civilizational, and educational but also through discourses of health, hygiene, and well-being. Indeed, during the late nineteenth century, there were neither modern hospitals nor doctors in many Ottoman territories, except in some larger cities. Identifying this deficiency as an opportunity, the American Board dispatched missionary doctors to their stations and opened hospitals and dispensaries. By the early twentieth century, they managed about ten hospitals and an equal number of dispensaries, with the largest in Anatolia in Antep, Elazig, and Merzifon. With over 30,000 patients visiting them on average three times per year, charitable exchanges with locals were frequent and abundant as those of means who were treated were charged while the poor received free care. Through healthcare, missionaries solidified their relations with locals but also left enduring influences in medicine and public health. Based on my collection and analysis of documents from the American Board, my paper renders a critical view of the American Protestant project in Ottoman lands during the nineteenth and early-twentieth centuries in terms of prevailing health conditions and epidemic diseases, the practice and politics of quarantine, the missionaries’ own roles in shaping the fields of health and medicine in the region, and their engagements with Ottoman authorities and local and Ottoman responses.