Microglia cells, the resident macrophages of the central nervous system, are key actors for specific brain functions that are critical for development and health. Microglial reactivity and functions, even when immature, play a major role if the developing brain is subjected to abnormal perinatal events. Brain exposure to general anesthesia, surgery, or analgesic drugs during early infancy may adversely affect its maturation and plasticity after injury. A better understanding of the regulation of microglial activation in the developing brain and interactions with specific anesthetic drugs is expected to give novel insights into the mechanisms underlying their potential adverse effects. This review recapitulates the most frequent perinatal circumstances associated with exacerbated systemic inflammation and neuroinflammation together with the double-edged role of microglia associated with subsequent brain damage. A role for microglial reactivity in both potential anesthetic toxicity and neuroprotection is emerging. However, further preclinical experiments are needed to better understand regulatory mechanisms of the developing microglia, and interaction between anesthesia and neuroinflammation in the developing brain.