In this study, we demonstrated the following results: (1) the levels of TRPV1 is higher in NSCLC; (2) TRPV1 overexpression induced DDP and 5-FU resistance in A549 cells independent of its channel function; (3) TRPV1 expression is increased in A549-DDP/5-FU resistant cells; (4) TRPV1 knockdown reversed the DDP/5-FU resistance in A549-DDP resistant cells; (5) TRPV1 overexpression induced DDP and 5-FU resistance by upregulation of the drug transporter ABCA5, enhancing DNA repair via the homologous recombination (HR) pathway, and increasing IL-8 release. Here, CXCL8 is linked to non-small cell lung carcinoma.