Background <p>Osteosarcoma (OS), the most common primary malignant bone tumor in adolescents, exhibits high metastasis and poor response to current therapies. DNA Ligase I (LIG1), a key enzyme in DNA replication and repair, has been implicated in multiple cancers, but its role in OS remains unclear.</p> Methods <p>Transcriptomic and clinical data from the TCGA–OS cohort were analyzed to assess LIG1 expression, immune infiltration, and prognosis. Functional studies using gain- and loss-of-function assays evaluated its impact on OS cell viability, clonogenicity, and apoptosis. The effects of LIG1 inhibition by epigallocatechin gallate (EGCG) were also examined.</p> Results <p>LIG1 was significantly upregulated in OS tissues and correlated with reduced overall and disease-free survival. High LIG1 expression was linked to an immunosuppressive microenvironment with fewer cytotoxic T cells and increased Tregs and M2 macrophages. Functionally, LIG1 promoted OS cell proliferation and survival, while its inhibition by EGCG suppressed tumor growth.</p> Conclusions <p>LIG1 drives OS progression and immune evasion by remodeling the tumor microenvironment. It serves as an independent prognostic biomarker and a potential therapeutic target, particularly in combination with immune checkpoint blockade.</p> Graphical Abstract <p></p>