The cAMP response element-binding protein (CREB) is a crucial transcription factor that regulates cell survival, synaptic plasticity, and immune responses in the central nervous system (CNS). Recent studies have highlighted its key role in modulating microglial polarization, a pivotal process in neuroinflammation. CREB activation promotes the anti-inflammatory M2 phenotype by upregulating IL-10 and Arg-1, while repressing M1-associated pro-inflammatory genes such as TNF-α and COX-2. Beyond these direct transcriptional effects, CREB functions as a signalintegration hub that interfaces with cAMP/PKA, NF-κB, PI3K/Akt and MAPK cascades, and cooperates with metabolic regulators, including PGC-1α, Nrf2 and PPARγ, to coordinate mitochondrial function and redox balance. CREB also influences neurotrophic factor expression (e.g., BDNF and NGF), inflammasome activity, and phagocytic responses, thereby coupling microglial states to neuronal survival. This review summarizes current advances in the molecular mechanisms of CREBregulated microglial polarization and discusses how these pathways contribute to CNS disorders such as Alzheimer's and Parkinson's disease, cerebral ischemia, multiple sclerosis, affective disorders, and pain-related disorders. Finally, we outline emerging CREB-targeted pharmacological and biological strategies, and highlight key knowledge gaps and safety considerations that must be addressed before CREB-based modulation of microglia can be translated into effective neuroimmune therapies.