Bone defects caused by trauma, infection, tumour resection and impaired healing remain difficult to reconstruct because successful repair requires coordinated mechanical stability, vascularisation, immune regulation and osteogenesis. Natural-based hydrogels provide hydrated, extracellular-matrix-mimicking platforms that can conform to irregular defects and integrate local delivery of bioactive factors, cells, extracellular vesicles and mineral phases. This critical narrative review examines natural-based hydrogels for bone regeneration from a biomaterials-to-clinic perspective, focusing on material design, cell–material interactions, vascularisation, osteoimmunomodulation, controlled therapeutic delivery, injectable and stimuli-responsive systems, composite reinforcement and 3D bioprinting. Human evidence exists for selected gelatin- and hyaluronan-based systems and for clinically adjacent applications such as growth-factor-assisted fracture healing and antibacterial implant coatings; however, most multifunctional regenerative systems remain preclinical. We therefore emphasise translational maturity rather than technological novelty alone. Key barriers include insufficient load-bearing mechanics, variable in vivo degradation, vascularisation at clinically relevant scale, manufacturing and sterilisation constraints, regulatory complexity and limited comparative clinical evidence. The most credible path to clinical adoption is likely to involve indication-specific systems that provide a reproducible biological advantage while remaining surgically compatible, scalable and practically manufacturable.