Islam is a religion that teaches universal and comprehensive truth, which includes aspects of creed, sharia, and morals. Islam also appreciates and recognizes the role of science in enriching man's knowledge of the universe and himself. The purpose of the study is to know the academic and theological challenges of the integration of Islam, science and culture of the archipelago. Literature research is used in this work, using books related to the topic under study as sources and research materials. The results of the study are academic challenges covering epistemology, ontology, axiology, and methodology, which require efforts to blend modern scientific approaches with Islamic values and worldviews and Nusantara culture. Theological challenges raise crucial questions about how to integrate Islamic religious beliefs with science and cultural values of the archipelago. It includes the interpretation of sacred texts, the concept of Divine creativity, visions of human beings, views on the universe, ethics, and approaches to scientific controversies. It is important to emphasize that this integration is not an attempt to eliminate uniqueness or replace existing traditions, but rather an attempt to enrich and expand man's understanding of the universe and its role in it. It requires open dialogue, open-mindedness, and in-depth study involving various disciplines, religions, and cultures to achieve a balanced integration and benefit the people of the archipelago and the world at large.