Malignant gliomas are the most common and devastating primary brain tumors in adults. The rapid invasion of tumor cells into the adjacent normal brain tissues is a major cause of treatment failure, yet the mechanisms that regulate this process remain poorly understood. MicroRNAs have recently emerged as regulators of invasion and metastasis by acting on multiple signaling pathways. In this study, we found that miR-622 is significantly downregulated in glioma tissues and cell lines. Functional experiments showed that increased miR-622 expression reduced glioma cell invasion and migration, whereas decreased miR-622 expression enhanced cell invasion and migration. Moreover, activating transcription factor 2 (ATF2), an important transcription factor that regulate tumor invasion, was identified as a direct target of miR-622. Knockdown of ATF2 using small interefering RNA recapitulated the anti-invasive function of miR-622, whereas restoring the ATF2 expression attenuated the function of miR-622 in glioma cells. Furthermore, clinical data indicated that miR-622 and ATF2 were inversely expressed in glioma specimens. Our findings provide insight into the specific biological behavior of miR-622 in tumor invasion and migration. Targeting miR-622/ATF2 axis is a novel therapeutic approach for blocking glioma invasion.