Background and purpose: Ginkgolide C (GGC) isolated form Ginko biloba (Ginkgoaceae) leaf can demonstrate pleiotropic pharmacological actions although. its anti-oncogenic impact in non-small cell lung cancer (NSCLC) model has not been reconnoitered. As signal transducer and activator of transcription 3 (STAT3) cascade can promote tumor growth and survival, we contemplated that GGC may interrupt this signaling cascade to expend its anti-cancer actions in NSCLC. Experimental approach: The effect of GGC on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of GGC on the growth of human NSCLC xenograft tumors in athymic nu/nu female mice was also investigated. Key results: GGC attenuated the phosphorylation of STAT3 and varying upstream kinases effectively. Exposure to pervanadate modulated GGC-induced down-regulation of STAT3 activation and promoted an elevation in the level of PTP protein. Indeed, silencing of the PTPgene reversed the GGC-promoted abrogation of STAT3 activation and apoptosis. Moreover, GGC exposure significantly reduced NSCLC tumor growth without demonstrating significant adverse effects via decreasing levels of p-STAT3 in mice tissues. Conclusions and Implications: Overall, the findings support that GGC may exhibit anti-neoplastic actions by mitigation of STAT3 signaling cascade in NSCLC.