Glioblastoma multiforme (GBM), WHO grade IV astrocytoma, is the most common primary neoplasm of the central nervous system (CNS) and has the highest malignancy and mortality rates. The invasive nature of GBM complicates surgical resection and restricts chemotherapeutic access, contributing to poor patient prognosis. The migration of tumor cells is closely related to the tumor cell proliferation. The acquisition of migratory capability, in addition to intracellular factors, is proposed to be a crucial mechanism during the progression of invasion. Using qRT-PCR analysis, we determined that the expression of miR-451 in glioma tissue was lower than in control brain tissue, especially in the central portions of the tumor. In glioma cell lines, we found that decreased miR-451 expression suppressed tumor cell proliferation but enhanced migration with a concomitant low level of CAB39/AMPK/mTOR pathway activation and high level of Rac1/cofilin pathway activation, respectively. Notably, the effect of miR-451 on cytological behavior and on the activation of mTOR and Rac1 was limited when AMPKα1 expression was knocked-down with a synthetic shRNA. We suggest that the glioma microenvironment results in heterogeneity of miR-451 expression. Our data indicated that miR-451 relays environmental signals by upregulating the activity of AMPK signaling, thereby modulating the activation of mTOR and Rac1/cofilin which, in turn, play key roles in glioma cell proliferation and migration, respectively. Our results highlight the need to consider opposing roles of a therapeutic target which, while suppressing tumor cell proliferation, could also promote cell infiltration.