Background and Purpose: While the prevalence of breast cancer metastasis in the brain is significantly higher in triple-negative breast cancers (TNBCs), there is a lack of novel and/or improved therapeutic approaches for these patients. Here, we explore the role of monoacylglycerol lipase (MAGL) in tumor growth and colonization in the brain. Experimental Approach: MAGL inhibitor AM9928 was selected for these studies due to its high specificity (hMAGL IC50 = 9nM). The effects of AM9928 on TNBC adhesion and transmigration across a 3D culture with human brain microvascular endothelial cells (BMECs) and the secretion of chemokines/cytokines were examined. The effects of AM9928 on TNBC tumor growth and tumor colonization in vivo in the brain were performed using TNBC mice models. Key Results: The residence time based on NMR time course data for AM9928 is 46 hours indicating prolonged pharmacodynamic effect. AM9928 blocked TNBC cell adhesion and transmigration across HBMECs in a 3D culture. AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells and from HBMECs cultures exposed to TNBC-derived exosomes. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood-brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in the brain. Together, these results demonstrate inhibition of TNBC tumor growth and brain colonization by AM9928 and support the potential clinical application of MAGL inhibitors as a novel treatment for TNBC.