Chronic inflammation in skeletal muscle is associated with impaired muscle regeneration and progressive weakness. However, the molecular mechanisms driving defective myogenesis remain incompletely understood. Here, we identify interferon-inducible protein 202 (IFI202) as a mediator of inflammation-associated myogenic dysfunction. Analysis of public RNA-sequencing datasets revealed that IFI16, the human ortholog of murine IFI202, is significantly upregulated in skeletal muscle from patients with inflammatory myopathies and Duchenne muscular dystrophy, suggesting a conserved role in human muscle pathology. Functionally, recombinant IFI202 impaired myogenic progression in primary skeletal muscle stem cells, as evidenced by sustained MyoD expression and reduced Myogenin expression, indicating defective myogenic differentiation. Mechanistically, recombinant IFI202 induced ERK and NF-κB phosphorylation in C2C12 myoblasts, and these effects were attenuated by pharmacological inhibition of TLR2 with C29 or OxPAPC, supporting the involvement of TLR2-dependent downstream signaling. Collectively, our findings demonstrate that IFI202 acts as a regulator of myogenesis by activating TLR2-driven signaling, thereby impairing muscle regeneration. These results provide new insight into the molecular mechanisms underlying defective myogenesis under chronic inflammatory conditions in skeletal muscle and identify IFI202/IFI16 as a potential therapeutic target.