This paper examines the role of medical knowledge in discussions of religious scepticism and materialism, by two medically trained Syrian Christian writers of the mid-nineteenth century. These writers’ professional medical knowledge was deployed to counter sceptical and materialist arguments and reaffirm their religious faith, but in ways which radically shifted the ground on which religious debate was conducted. The Damascene Mikha’il Mishaqa (1800-1888) was raised at the court of Emir Bashir Shihabi of Mount Lebanon and Greek Catholic circles, in which he received an informal education in medicine and began practising as a physician. He later received a newer style of medical training at the Egyptian government’s medical school in Cairo; read many of the medical translations made there; and had contact with American Protestant missionary doctors around the time of his conversion to Protestantism in 1849. In an 1853 tract directed against religious scepticism, he used medical examples as well as ones drawn from other natural sciences and mathematics to demonstrate the weakness of human reason and the necessity of a divine revelation. In his little-known, unpublished correspondence with American missionary Eli Smith, he explained the medical reasoning behind these arguments more fully, shedding light on his views on both the consistency of natural laws and the action of medicinal cures on the body. The Aleppine Greek Catholic Fransis Marrash (1836-1873) was apprenticed to the Protestant missionary doctor John Wortabet, and later studied medicine in Paris. In his 1865 utopian narrative and a posthumously published anti-Darwinist tract, he used his medical knowledge to draw analogies between the human and natural worlds, and to grapple with the problems posed by materialist doctrines. He ultimately arrived at a rejection of materialism in favour of religious faith, based partly on scientific reasoning. These arguments fit within a wider interest in medicine and the natural sciences in the Aleppine Christian circle to which Marrash belonged. Both Mishaqa and Marrash, while reaffirming their religious faith through their use of medical and scientific knowledge, took religious discourse into a very different terrain to that of earlier religious polemics, which focussed far more on issues of doctrine and revelation. The possibilities of religious scepticism and materialism as coherent positions were now acknowledged, and the relevance of medico-scientific evidence for judging religious truths was accepted. These debates thus form part of the prehistory of the better-known discussions of Darwinism and Büchnerian materialism in the later nineteenth century.