<p>Skeletal muscle repair after injury requires coordinated immune responses. The cannabinoid type 2 receptor (CB2R) has been implicated in this process; however, its molecular mechanism in regulating inflammation and muscle regeneration, particularly whether it involves modulating macrophage pyroptosis—a specific pro-inflammatory cell death—remains elusive. This study proposes and validates a novel mechanism: CB2R activation protects skeletal muscle by inhibiting the PI3K/AKT/NF-κB signaling axis, thereby suppressing NLRP3 inflammasome-mediated pyroptosis in macrophages and ultimately fostering a pro-regenerative microenvironment. Using a mouse contusion model and conditioned medium assays, we demonstrate that CB2R deficiency exacerbates macrophage pyroptosis, elevates inflammatory mediators, and impairs muscle repair. This effect is driven by hyperactivation of the PI3K/AKT/NF-κB pathway, as blocking this pathway alleviated the inflammatory response and restored the expression of muscle regeneration markers. Furthermore, inflammatory signals released from CB2R-deficient macrophages directly impaired the development of muscle cells in the conditioned medium-based assay. Our findings uncover a novel non-cell-autonomous mechanism whereby CB2R supports skeletal muscle regeneration by restraining macrophage-driven inflammation and maintaining a repair-permissive environment, providing new insights into skeletal muscle repair from the perspective of the regenerative microenvironment and further expand the current understanding of muscle regeneration following injury. This work provides a robust mechanistic rationale for repurposing CB2R agonists as promising therapeutic strategies for muscle injury.</p>