American missionaries have long been the missing link in the study of the late Ottoman era despite the fact that they left their enduring mark in American conceptions of the period. From the landing of the first American Protestant missionaries on the Ottoman Empire, as a matter of fact on the Middle East, in early 1820, until the outbreak of the First World War, American missionaries occupied the increasing attention of the Ottoman bureaucracy in domestic and foreign affairs while the mission work in the Ottoman Empire established the largest investment of the American Board globally, even above China and India, before the war. The bulk of the correspondence of the Ottoman Foreign Affairs Ministry for the time period in question was with the United States and this was chiefly concerned about the American mission schools. Therefore, this paper seeks to examine the encounter between the Ottoman officialdom and the American Protestant missionaries primarily operating under the American Board in Ottoman Turkey during the regimes of Abdulhamid II and the Unionists respectively in 1876-1914 and pursues a two-fold aim. First, it sheds light on the activities of the American Board, mainly the schools, and addresses the concerns and reactions of the Ottoman central and provincial authorities to American missionaries and their establishments. The study shows that Ottomans endeavored to counter the missionaries via a set of prohibitive and punitive legal acts and regulations and to compete with their enterprise via a new line of programs and institutions such as schools. Second, the paper demonstrates how the missionaries were instrumental in the orientation of the American foreign policy towards the Ottomans and attests that support of the American government for the mission work in Ottoman lands were explicit and forceful even to the extent of sending war vessels to the Ottoman ports six times under three different Presidents in a ten-year period. The study draws archival materials largely from the Prime Ministry’s Archives in Istanbul and from the U.S. Department of State collections, the Burke Library at Union Theological Seminary, and the Houghton Library in Harvard University. The paper concludes that the very agenda of the missionaries, namely, to evangelize the Muslims of the Ottoman Empire, which remained dormant throughout the nineteenth century, resurfaced on the eve of the First World War given the drastic change in ethno-religious map of the Ottoman Empire in favor of Turks and Muslims.