Background <p>Radiotherapy remains a cornerstone for non‑small cell lung cancer (NSCLC). However, its efficacy is frequently limited by radioresistance, a phenomenon closely associated with cancer stem-like cells (CSCs). Although our previous work demonstrated that epicatechin (EC) sensitizes NSCLC cells to ionizing radiation (IR), whether this effect involves modulation of CSCs and the underlying mechanisms remain to be elucidated.</p> Methods <p>A radioresistant NSCLC cell line (A549RR) was established via fractionated irradiation and employed in both in vitro assays and murine xenograft models. To assess its radiosensitizing potential, EC was administered prior to IR exposure. Cell viability and colony formation capacity were measured to evaluate radiosensitivity. Putative targets of EC were predicted using network pharmacology and validated through molecular docking. The direct interaction between EC and CXCL8 was examined by cellular thermal shift assay (CETSA). The functional relevance of CXCL8 in EC-mediated effects was assessed through both loss-of-function (shRNA-mediated knockdown) and gain-of-function (CXCL8 overexpression) approaches. CSC properties were evaluated by tumor sphere formation assays and immunoblotting for stemness markers.</p> Results <p>EC significantly enhanced NSCLC radiosensitivity both in vitro and in vivo, concomitant with marked suppression of CSC stemness. CXCL8 was identified as a direct functional target of EC: its expression was substantially upregulated in radioresistant cells but downregulated upon EC treatment. CETSA confirmed a direct interaction between EC and CXCL8 in cells. Functionally, CXCL8 knockdown suppressed cell viability, colony formation capacity, and CSC properties in A549RR cells. Conversely, overexpression of CXCL8 abrogated EC-induced radiosensitization and restored CSC phenotypes in both cellular and xenograft models.</p> Conclusion <p>EC overcomes NSCLC radioresistance by directly targeting CXCL8, thereby disrupting CSC-like traits.</p>