<p>The protective impact and unique mechanisms of human umbilical cord mesenchymal stem cells (HUC-MSCs) transplantation following hypoxic-ischemic (HI)-induced brain white-matter injury (WMI) were explored. To establish a WMI model, Sprague-Dawley rats with three days after birth underwent unilateral carotid artery ligation, followed by hypoxic exposure (8% oxygen and 92% nitrogen). Subsequently, HUC-MSC transplantation was performed into the lateral ventricle. Molecular and behavioral experiments were conducted to assess how it would influence NLRP3 inflammasome activation, M1/M2 microglial polarization, and spatial cognitive abilities. HUC-MSCs promoted myelin regeneration and improved spatial cognitive function by blocking NLRP3 inflammasome activation. Furthermore, HUC-MSCs modified microglial polarization away from the M1 phenotype by downregulating the expression of CD86 and iNOS proteins and attenuating the release of proinflammatory cytokines such as TNF-α and IL-1β. They promoted anti-inflammatory cytokine production, such as TGF-β and IL-10, and the upregulation of CD206 and Arg-1 protein expression, thereby helping microglia transition to the M2 phenotype. HUC-MSCs inhibited NLRP3 inflammasome activation by antagonizing TLR4 receptors, induced microglial polarization towards the M2 phenotype in neonatal rats with WMI. HUC-MSCs seem to be a promising therapeutic option for treating WMI in premature infants.</p>