Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascades is considered to be a rational therapeutic and preventive strategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components, including -shogaol, -paradol and -gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, -shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. -Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, -shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, -shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclin D1/3, which are target proteins in the Akt signaling pathway. The induction of apoptosis in NCI-H1650 cells by -shogaol corresponded with the cleavage of caspase-3 and caspase-7. Moreover, intraperitoneal administration of -shogaol inhibited the growth of NCI-H1650 cells as tumor xenografts in nude mice. -Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that -shogaol can be exploited for the prevention and/or treatment of NSCLC.