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Neuroinflammation is associated with the pathogenesis of all types of neurological disease, in which microglial cells play a critical role. In response to disturbances in the microenvironment, microglia (MG) become activated and differentiate into either an M1 phenotype, which has a proinflammatory damaging effect, or an M2 phenotype, which plays an anti-inflammatory and reparative role. Thus, modulating microglial polarization is a suitable strategy to treat neuroinflammatory disorders. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects during neurological diseases. In this study, we predicted that adipose-derived stem cells (ADSCs) could produce GDNF and investigated the effects of GDNF on microglial M1/M2 polarization. Furthermore, we determined whether GDNF modulates microglial activation and polarization via the phosphoinositide-3-kinase (PI3K)/AKT signaling pathway. We found that the secretion of inflammatory cytokines in lipopolysaccharide-stimulated MG was downregulated, whereas the antiinflammatory mediators in interleukin-4-stimulated MG were upregulated obviously, following pretreatment with ADSCs or GDNF. In addition, GDNF produced by ADSCs inhibited the MG M1 phenotype and promoted the M2 phenotype by upregulating the PI3K/ATK pathway. These results reveal that GDNF produced by ADSCs might be useful for the regulation of neuroinflammatory disorders.