In this study, the effects of hypoxia-inducible factor-1α (HIF-1α) on gastric carcinoma (GC) drug resistance through apoptosis-related genes are investigated. First, HIF-1α-specific siRNA was synthetized and transfected into drug-resistant GC cell line OCUM-2MD3/L-OHP. Then MTT assay was applied to test the inhibition rate of GC cells by 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). After that, flow cytometry (FCM) was applied to measure apoptosis rate. qPCR and Western blot assay were employed to detect HIF-1α and apoptosis-related genes. Results showed that HIF-1α in OCUM-2MD3/L-OHP cells was higher than that in OCUM-2MD3 and gastric epithelial cells. After HIF-1α-siRNA transfection, inhibition rates of 5-FU and L-OHP to tumor cells increased significantly. FCM results showed that apoptosis rate of OCUM-2MD3/L-OHP cells increased significantly. After HIF-1α-siRNA transfection, survivin and Bcl-2 decreased, whereas Bax, caspase 3, and caspase 8 increased significantly. Results from this study seem to confirm that HIF-1α getting involved in GC drug resistance is possibly due to its regulation of some apoptosis-related genes. HIF-1α may be a potential target to reverse drug resistance of GC.