There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPR/Cas9 screening and identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC and improved the efficacy of chemotherapy. Based on the highest single agent model, the CDC7 inhibitor XL413 had a synergistic effect with both cisplatin and etoposide in chemo-resistant SCLC cells, but had no such effect in chemo-sensitive SCLC cells; the combination of XL413 and chemotherapy significantly inhibited cell growth. Western blot and flow cytometry showed that the combined treatments increased apoptosis, whereas XL413 alone had little effect on apoptosis. An analysis of cell cycle and cyclin protein levels indicated that the combination of XL413 and chemotherapy-induced G1/S phase arrest and DNA damage in chemo-resistant SCLC cells. Xenografted tumor and histoculture drug response assays using patient-derived xenografts showed that XL413 improved the efficacy of chemotherapy in vivo and with SCLC tissues. These results suggest that XL413 exerts a synergistic effect with chemotherapy on chemo-resistant SCLC.