Purpose <p>Hypoxia is an inevitable consequence of surgical interventions such as bone augmentation and soft tissue transplantation in oral and maxillofacial surgery. Cellular adaptation to hypoxic conditions critically influences regenerative processes, including osseointegration, angiogenesis and tissue integration. This systematic review investigated the effects of hypoxic conditions and hypoxia-regulating strategies on tissue regeneration, with the aim of identifying mechanisms to enhance clinical outcomes.</p> Methods <p>Following the PRISMA guidelines, a systematic search was performed in MEDLINE (via PubMed), Cochrane, and Web of Science up to 31st May 2025, including reference list and citation screening. The risk of bias was assessed according to the SYRCLE risk of bias tool.</p> Results <p>Of 5790 studies, 9 met the inclusion criteria. These studies investigated various interventions, including gene therapy targeting hypoxia-inducible factor 1α (HIF-1α), oxygen-releasing biomaterial scaffolds, hyperbaric oxygen treatment and hypoxia preconditioning of bone marrow mesenchymal stem cells. Some studies showed enhanced bone formation and vascularization with HIF-1α upregulation or hypoxic preconditioning, while others highlighted HIF-1α’s role in osteoclast activation and bone resorption. Hyperbaric oxygen treatment consistently improved bone healing.</p> Conclusion <p>Current evidence highlights a complex interplay between hypoxia and regenerative outcomes in oral and maxillofacial surgery. Although modulation of HIF-1α and the hypoxic microenvironment hold promise, further research is needed to clarify optimal strategies for maximizing benefits and minimizing detrimental effects.</p> Clinical relevance <p>The ability to influence the HIF pathway in beneficial manner may be a cornerstone to unlocking the next generation of regenerative therapies in oral and maxillofacial surgery.</p>