Large bone defects resulting from fractures and disease are a major clinical challenge, being often unable to heal spontaneously by the body's repair mechanisms. Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration. However, replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells. Therefore, reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair. Herein, we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels (CPP-L/GelMA) as a “bone microenvironment regulative hydrogel” to reverse the hypoxic microenvironment in bone defects region. CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase (CAT) and ROS-responsive oxygen-releasing nanoparticles (PFC@PLGA/PPS) co-loaded liposome (CCP-L) and GelMA hydrogels. Under hypoxic condition, CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks. The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis. Finally, CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway. Hence, CPP-L/GelMA, as a bone microenvironment regulative hydrogel for bone tissue respiration, can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region, possessing of great clinical therapeutic potential.