Background/Objective: New therapeutic targets are urgently needed for glioblastoma, the most aggressive primary brain tumor in adults. Monepantel (MPL), a repurposed anthelmintic, is thought to act in cancer cells through ATF4-mediated endoplasmic reticulum (ER) stress that inhibits mTORC1, but this axis had not been examined in glioma. The present study aimed to evaluate the effects of monepantel (MPL) in rat C6 glioma and human U87-MG glioblastoma cells, focusing on the ER stress/mTOR/autophagy signaling network. Methods: Cells were treated with MPL, and cell viability was measured by MTT assay. The signaling pathways were analyzed by Western blotting, and autophagy by acridine orange staining and LC3-II detection. Cell migration was assessed using a scratch wound-healing assay and tumorspheres. Results: MPL increased the ER chaperone BiP/GRP78 and induced autophagy, as shown by concentration-dependent accumulation of acidic vesicular organelles and LC3-II. In parallel, MPL reduced phosphorylation of the mTORC1 substrate p70S6K, without affecting Akt, localizing its action at or below mTORC1, suggesting an ER-stress-to-autophagy route. MPL additionally produced a decrease in ERK2 phosphorylation, while p38^MAPK was unchanged. These molecular changes were accompanied by reduction in C6 viability and by impaired C6 migration and reduced U87-MG tumorsphere migratory area. Conclusions: Together, these data suggest that MPL engages an ER-stress/mTORC1 axis associated with autophagy and ERK2 inhibition in glioma. These findings indicate the potential of MPL as an antiglioma agent. However, further studies using additional cell lines, together with preclinical testing, are needed to better characterize its effects and determine its potential for future clinical application.