Glioblastoma multiforme (GBM) is the most common and aggressive form of glioma, accounting for approximately 50% of all malignant brain tumors. The GBM tumor microenvironment (TME) is a highly complex, dynamic ecosystem of multiple cell types and signaling mediators that play a crucial role in development and progression of the disease. Microglia are abundant in the GBM TME, and their activation induces production of inflammatory mediators that favor tumor progression. Regulator of G protein Signaling 10 (RGS10) is highly enriched in microglia where it suppresses the expression of multiple proinflammatory genes associated with the GBM TME. Among these, RGS10 has been shown to regulate the significant inflammatory enzyme cyclooxygenase 2 (COX-2) and its subsequent product, the bioactive lipid prostaglandin E2 (PGE2). COX-2/PGE2 is often upregulated in the GBM microenvironment and is associated with therapeutic resistance, immunosuppression, and poor prognosis. The anti-inflammatory role of RGS10 makes it a prime candidate for a potential therapeutic target in the GBM tumor microenvironment. Our previous work has demonstrated that RGS10 strongly suppresses lipopolysaccharide (LPS)-induced COX-2/PGE2 in microglia (this suppression is independent of its canonical G protein-targeted mechanism). In this study, we sought to demonstrate the effect of microglial RGS10 inflammatory mediator regulation on the GBM tumor microenvironment. Here, we sought to investigate the impact of microglial RGS10 inflammatory mediator regulation on the GBM tumor microenvironment. Here we demonstrate for the first time that secretory mediators regulated by RGS10 suppress COX-2 in an autocrine/paracrine manner. We further demonstrate RGS10 regulated secretory mediators significantly increase COX-2 in GBM cells. We show evidence that microglial RGS10 regulation suppresses GBM cell migration in coculture and attenuates chemotherapeutic resistance in GBM cells. We establish RGS10 is regulating inflammatory mediators that increase GBM-TME associated prognostic markers. We report that RGS10’s regulatory role directly impacts GBM proliferation/migration/signaling in a microglial specific COX-2 dependent manner. Collectively, these results exhibit the ability of microglial RGS10 to suppress COX-2 in the GBM tumor microenvironment and have a significant effect on multiple facets of GBM tumor progression indicating that RGS10 could be a viable therapeutic target in GBM.