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Abstract This work represents the first comprehensive examination of C. S. Lewis’s views on the relationship between science and religion. It focuses on both the literary depictions of this relationship and its significance in cultural discussions regarding the boundaries of human knowledge, as well as Lewis’s understanding of the roles of science and religion in humanity’s pursuit of meaning and significance. This study provides a rigorous and historically informed analysis of Lewis’s account of the interplay between science and religion in his studies of medieval and Renaissance literature and his literary and philosophical explorations of modern naturalism and materialism. The work breaks fresh ground in exploring Lewis’s appeal to scientific criteria for evaluation in his apologetics, in which he anticipates the approach now known as ‘inference to the best explanation’, which was not formally articulated until after Lewis’s death. While some continue to characterize Lewis as an anti-scientific Luddite entrenched in a bygone world of medieval fantasies, this analysis makes it clear that Lewis was well acquainted with both the cultural perceptions of science and religion during the medieval and Renaissance eras, as well as the major philosophical and cultural debates of the twentieth century.