Neurodegenerative diseases (NDs), such as Alzheimer's and Parkinson's, are characterized by chronic inflammation and oxidative stress, often mediated by activated microglial cells. Microglia-induced neuroinflammation is essential to neuronal damage, driven by the overproduction of pro-inflammatory cytokines and reactive oxygen species. Autotaxin (ATX), a lysophospholipase D enzyme, can modulate inflammation through its enzymatic product lysophosphatidic acid (LPA). While previous studies highlighted ATX's anti-inflammatory properties, its impact on P-glycoprotein (P-gp), a key efflux transporter involved in drug resistance and neuroinflammation, remains not fully understood. The objective of this study was to explore how ATX modulates the expression and activity of P-gp in lipopolysaccharide (LPS)-activated and H2O2-stressed BV-2 microglial cells. Microglial cells were transfected with either an empty vector (EV) or an ATX cDNA vector (A +) and exposed to LPS (1 µg/mL) or H2O2 (100 µM). The mRNA expression levels of P-gp and pro-inflammatory cytokines were analyzed using qRT-PCR, and P-gp activity was assessed using the NBD-CSA fluorescence efflux assay. Our findings revealed that while LPS- and H