<p>The escalating depletion of fossil fuel reserves and mounting environmental concerns from greenhouse gas emissions have intensified the global pursuit for sustainable energy alternatives. Bio-hydrogen production emerges as a transformative solution, offering carbon–neutral energy generation while simultaneously addressing organic waste management challenges. This comprehensive review examines the revolutionary integration of nanotechnology, advanced microbial engineering, and circular economy principles in bio-hydrogen production systems. A systematic analysis of diverse renewable feedstocks, including agricultural residues, municipal solid waste, microalgae, and industrial biomass, highlighting their potential for decentralized bio-hydrogen production. The review critically evaluates cutting-edge microbial innovations encompassing hybrid fermentation systems, extremophile consortia, and synthetic biology approaches utilizing CRISPR-Cas9 technology for enhanced hydrogen yields. Nanotechnology applications are extensively discussed, focusing on nano-metal catalysts, enzyme immobilization techniques, and plasmonic nanoparticles that significantly improve bioconversion efficiency and system stability. Advanced purification technologies, including mixed-matrix membranes and graphene-based systems, alongside innovative storage solutions using metal hydrides, are comprehensively assessed. The integration of bio-hydrogen into fuel cells and industrial applications demonstrates substantial potential for replacing fossil-based hydrogen. This review establishes bio-hydrogen as a cornerstone technology for achieving sustainable energy transitions while fostering circular bio-economy development.</p>