<p>Chronic pain has emerged as a disorder of persistent neuroimmune dysregulation, with microglia playing a pivotal role in shaping maladaptive plasticity. Beyond classical inflammatory pathways, recent discoveries highlight microglial involvement in epigenetic remodeling, metabolic reprogramming, and synaptic modulation. These multidimensional processes sustain microglial activation and promote central sensitization, even in the absence of ongoing peripheral injury. This review proposes a comprehensive framework for understanding microglial regulation in chronic pain, emphasizing the failure of immune tolerance, aberrant neuron–glia signaling, and the emergence of disease-perpetuating microglial states. We further discuss therapeutic strategies aimed at selectively targeting microglial phenotypes, including HDAC inhibitors, metabolic modulators, and pathway-specific antagonists. By integrating mechanistic depth with translational insights, this review reframes microglia not only as inflammatory mediators, but as dynamic regulators whose dysregulation underlies pain chronification.</p>