Background <p>Lung cancer is the prime cause of cancer-related death worldwide. It is an aggressive malignant tumor characterized by significant dysregulation of various oncogenic and immunosurveillance pathways. STAT3 is considered to be a point of convergence of such pathways, so it is an attractive therapeutic target for lung cancer. Hence, the current study aimed to investigate the anticancer activity of baricitinib and/or rosuvastatin as repurposed drugs known to inhibit STAT3.</p> Methods and results <p>In vitro experiments were conducted using two NSCLC cell lines (A549 and H460), and the MTT test was used to assess the cytotoxic activity of both drugs and their combination. Moreover, selected oncogenic proteins were quantified. In addition, in vivo experiments were also performed using a urethane-induced lung cancer mice model. Both drugs showed excellent anticancer activities along with outstanding synergism when combined. Baricitinib and/or rosuvastatin inhibited cancer cell proliferation, migration, and angiogenesis in addition to inducing apoptosis. Furthermore, they exhibited immunoediting effects against cancer via significant suppression of PD-L1 and CTLA-4 inhibitory immune checkpoints.</p> Conclusion <p>The current study highlights the potential therapeutic benefits of baricitinib as an anticancer agent, for the first time, and/or rosuvastatin as repurposed drugs that can be used in lung cancer treatment.</p> Graphical abstract <p>Created in BioRender.El-hanboshy, S. (2025) <a href="https://BioRender.com/l95u186">https://BioRender.com/l95u186</a>.</p>