Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.