While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins including transactivator of transcription (Tat) contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for strategies to reduce resulting inflammation associated neurocognitive disorders, this study probed the therapeutic potential of inhibiting monoacylglycerol lipase (MAGL) to upregulate 2-arachidonoylglycerol (2-AG) and regulate inhibitory neuronal activity. In vitro, MAGL inhibitor MJN110 reduced hyperexcitability and increased dendritic branching complexity in Tat-treated frontal cortex neurons. In vivo, MJN110 administration increased 2-AG in the prefrontal cortex (PFC) and striatum across groups, and restored PFC N-arachidonoylethanolamine levels in Tat(+) subjects. While Tat increased reward-related learning in a novel cognitive flexibility assay, MJN110 altered reversal learning specifically in Tat(+) mice to rates indistinguishable from Tat(-) controls. Collectively, results suggest MAGL inhibition is neuroprotective against neuronal hyperexcitability, dendritic arborization simplification, and neurocognitive alterations driven by Tat.