Glioblastoma multiforme (GBM) is a lethal and aggressive cancer with an extremely poor prognosis. Recent preclinical, clinical, and genomic studies have highlighted the role of the Hippo-Yap pathway in the progression of GBM. In addition, it has been identified that YAP plays a major role in creating an immunosuppressive tumor microenvironment, facilitating drug resistance, recurrence, and metastasis of GBM tumors. In this study, we report that "moxidectin", an antihelminthic drug, inhibits the proliferation of SF268, SF295, SF188, and CT-2A-Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence data show that moxidectin mediates its effects by inhibiting the MEK-ERK pathway, a regulator of Hippo-YAP signaling. Inhibition of MEK-ERK by moxidectin ultimately led to blockade of the nuclear translocation and transcriptional activity of the YAP/TAZ-TEAD complex in various GBM cells. Oral administration of 3.5 mg/kg moxidectin suppressed the growth of GBM tumors by 90% in an intracranial tumor model. Ex vivo analysis of excised tumors confirmed the observations made in in vitro studies. Interestingly, moxidectin enhanced antigen presentation in the tumor-draining lymph nodes and reduced the pro-tumorigenic macrophage population in the brain, indicating that it might play a role in modulating the immune response. Chronic moxidectin treatment did not cause any toxicity in mice based on our toxicologic evaluation. Moxidectin is an FDA-approved drug, and findings from our study will promote its clinical investigation as a potential therapeutic agent for patients with GBM.