<p>The Nigerian leather industry, despite its vast resource base and economic potential, continues to rely heavily on traditional processing methods that pose significant environmental and health risks. This review paper provides an interdisciplinary examination of the biophysical and biochemical innovations as transformative tools for improving leather processing, with a focus on strategies for achieving sustainable industrial practices in Nigeria. From a biophysical perspective, the paper explores thermal and mechanical operations, spectroscopic monitoring techniques, and the role of nanotechnology in improving leather quality and processing efficiency. Biochemical and toxicological considerations are also addressed, particularly the health and ecological risks associated with chromium salts, aldehydes, and synthetic dyes. Natural and enzymatic alternatives are evaluated for their efficacy and environmental performance. Drawing on case studies from recent innovations in green chemistry, enzymatic tanning, and plant-based materials, this review synthesizes practical pathways for cleaner production. The review concludes by offering an integrated roadmap encompassing technological modernisation, policy reform, and institutional leadership—particularly the role of the Nigerian Institute of Leather and Science Technology (NILEST)—to support a science-led transition to sustainable leather manufacturing. Overall, this paper aims to guide stakeholders in academia, industry, and government in reforming Nigeria’s leather value chain for economic resilience and ecological stewardship toward a more sustainable and innovation-driven future.</p> Graphical abstract <p></p>