MicroRNAs can bind with target genes thus inhibiting their expression levels to regulate cell survival, hence serve as serum biomarkers for a variety of purposes. Our aim was to explore the role of miR-15a-5p in the cisplatin/oxaliplatin resistance of gastric cancer. In this study, the growth and apoptosis of gastric cancer cell lines were measured with cell viability assay and flow cytometry, respectively. Dual-luciferase assay was applied for miRNA target validation. Expression of PHLPP2 and miR-15a-5p were measured by quantitative polymerase chain reaction and western blot, respectively. Serum miR-15a-5p level of 82 gastric cancer patients was examined by qPCR. Our results indicated that miR-15a-5p overexpression increased cisplatin resistance of gastric cancer cells, whereas miR-15a-5p downregulation decreased the resistance. miR-15a-5p directly targets and inhibits PHLPP2 in gastric cancer cells, enhancing downstream Akt phosphorylation. Moreover, overexpression of miR-15a-5p could attenuate the decrease in cisplatin resistance induced by PHLPP2 overexpression. Additionally, we observed that lower serum miR-15a-5p level was significantly correlated with better response to oxaliplatin-based chemotherapy as well as better 3-year survival. In conclusion, miR-15a-5p was recognized as a biomarker for platinum resistance and prognosis in gastric cancer, interference of which may be a promising strategy for sensitizing gastric cancer to platinum drugs.