Background: This research explored the effects of vinorelbine combined with oxaliplatin on non-small cell lung cancer (NSCLC). Materials and Methods: NSCLC cells were treated with vinorelbine, oxaliplatin, and insulin-like growth factor-1 (IGF-1; phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway activator), and transfected with ATP-binding cassette subfamily G member 2 (ABCG2) overexpression plasmid and silenced ABCG2 (siABCG2). Cell viability was detected by cell counting kit-8 assay, cell migration and invasion by the transwell assay, and cell apoptosis by flow cytometry. Levels of ABCG2, PI3K, phosphorylation (p)-PI3K, AKT, and p-AKT were evaluated through qRT-PCR and western blot. Results: Co-treatment with vinorelbine and oxaliplatin exerted synergistic effects in suppressing the proliferation, migration, invasion, and the phosphorylation of PI3K and AKT, and inhibiting ABCG2 expression while inducing apoptosis in NSCLC cells. Overexpression of ABCG2 reversed these effects on proliferation, migration, invasion, and apoptosis, while not affecting the PI3K/AKT pathway in NSCLC cells. IGF-1 inhibited the synergistic effect of vinorelbine and oxaliplatin on the NSCLC cells. Moreover, siABCG2 reversed the effects of IGF-1 on ABCG2 expression, and other cellular functions mentioned above in NSCLC cells receiving the co-treatment. Conclusion: A combination of vinorelbine with oxaliplatin represses the proliferation, migration, and invasion of NSCLC cells, and facilitates apoptosis via inhibition of the PI3K/AKT/ABCG2 axis.