Background: Although aberrant expression of MRPS16 (mitochondrial ribosomal protein S16) contributes to biological dysfunction, especially mitochondrial translation defects, the status of MRPS16 and its correlation with prognosis in tumors, especially glioma, which is a common, morbid and frequently lethal malignancy, are still controversial. Methods: Herein, we used high-throughput sequencing to identify the target molecule MRPS16. Subsequently, we detected MRPS16 protein and mRNA expression levels in normal brain tissue (NBT) and different grades of glioma tissue. The molecular effects of MRPS16 in glioma cells were tested by Western blotting, quantitative polymerase chain reaction (qRT-PCR), EdU, CCK-8, colony formation, Transwell migration and invasion assays. Results: Intriguingly, we found that MRPS16 knockdown suppressed tumor cell growth, migration and invasion. Conversely, MRPS16 over-expression increased tumor cell growth, migration and invasion. In addition, subsequent mechanistic studies indicated that MRPS16 promoted glioma cell growth, migration and invasion by the activating PI3K/AKT/Snail axis. Furthermore, we observed that the decrease in tumor cell growth, migration, invasion and Snail expression mediated by MRPS16 knockdown could be rescued by Snail over-expression. Conclusion: In short, our data demonstrate that MRPS16 over-expression remarkably promotes tumor cell growth, migration and invasion via the PI3K/AKT/Snail axis, which may be a promising prognostic marker for glioma.