Neuroinflammation underlies the pathophysiology of multiple age-related neurological disorders. Microglia, the resident immune cells of the central nervous system, are critically involved in neuroinflammatory regulation and neural survival. Modulating microglial activation is thus a promising approach to alleviate neuronal injury. Our serial studies have revealed a neuroprotective role of the δ-opioid receptor (DOR) in several acute and chronic cerebral injuries by regulating neuroinflammation and cellular oxidative stress. More recently, we found an endogenous mechanism for the inhibition of neuroinflammation is closely related to DOR’s modulation of microglia. Our recent studies showed that DOR activation could strongly protect neurons from hypoxia- and lipopolysaccharide (LPS)-induced injury by inhibiting microglial pro-inflammatory transformation, while knocking-down DOR or restraining DOR activity promoted microglia activation and the relevant inflammatory events with an aggravation of cell injury. This novel finding highlights a therapeutic potential of DOR in numerous age-related neurological disorders through the modulation of neuroinflammation by targeting microglia. This review summarized the current data regarding the role of microglia in neuroinflammation, oxidative stress, and age-related neurological diseases focusing on the pharmacological effects and signaling transduction of DOR in microglia.