AimsPrevious studies have indicated that IFI30 plays a protective role in human cancers. However, its potential roles in regulating glioma development are not fully understood.MethodsPublic datasets, immunohistochemistry, and western blotting (WB) were used to evaluate the expression of IFI30 in glioma. The potential functions and mechanisms of IFI30 were examined by public dataset analysis; quantitative real‐time PCR; WB; limiting dilution analysis; xenograft tumor assays; CCK‐8, colony formation, wound healing, and transwell assays; and immunofluorescence microscopy and flow cytometry.ResultsIFI30 was significantly upregulated in glioma tissues and cell lines compared with corresponding controls, and the expression level of IFI30 was positively associated with tumor grade. Functionally, both in vivo and in vitro evidence showed that IFI30 regulated the migration and invasion of glioma cells. Mechanistically, we found that IFI30 dramatically promoted the epithelial–mesenchymal transition (EMT)‐like process by activating the EGFR/AKT/GSK3β/β‐catenin pathway. In addition, IFI30 regulated the chemoresistance of glioma cells to temozolomide directly via the expression of the transcription factor Slug, a key regulator of the EMT‐like process.ConclusionThe present study suggests that IFI30 is a regulator of the EMT‐like phenotype and acts not only as a prognostic marker but also as a potential therapeutic target for temozolomide‐resistant glioma.