Introduction: The mortality rate of glioma patients particularly with glioblastoma multiforme (GBM) remains high even with advancements in the multimodality treatment. This is partly due to chemoresistance of the glioma cells towards drug treatment which finally reduced the survival of GBM patients. In this study, we determined the chemosensitisation and oncogenic characteristics of ZFP36L2 in LN18 GBM cells using RNA interference (RNAi). Methods: Meta-analysis of microarray datasets was used to identify the druggable genes responsive to GBM chemosensitivity. Subsequently, the genes were validated using RNAi screening [pooled small interference RNA (siRNA)]. Temozolomide- resistant LN18 cells were used to evaluate the effects of gene silencing on chemosensitisation to the sub-lethal dose (1/10 of IC50) of temozolomide. Assays such as cell viability, proliferation, migration and invasion and apoptosis assays were carried out. The apoptosis pathway underlying chemosensitisation by ZFP36L2 siRNA was determined using a human apoptosis array kit. Statistical analyses were performed using one-way analysis of variance. Results: ZFP36L2 was identified as a potential marker of GBM based on the meta-analysis and RNAi screening. ZFP36L2 knockdown lead to 1) Apoptosis induction (p < 0.05) 2) Reduced cell migration (p < 0.05) 3) Reduced up to 82% of cell invasion (p < 0.01) and 4) Decreased cellular proliferation in siZFP36L2-treated LN18 cells. Downstream analysis showed that the sub-lethal dose of temozolomide caused major upregulation of BCL2-associated X, apoptosis regulator (BAX). Conclusion: ZFP36L2 is oncogenic and chemosensitive thus may contribute to gliomagenesis through cell proliferation, migration, invasion and apoptosis. RNAi therapy in combination with chemotherapy treatment such as temozolomide may serve as potential therapeutic approach in the future.