Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory glycoprotein expressed primarily in the liver and brain under homeostatic conditions and dysregulated in various CNS pathologies. Yet its cellular expression profile and physiological significance in postnatal development remain elusive. Here, we showed that Serpina3n protein is expressed predominantly in oligodendroglial lineage cells in the postnatal CNS and that oligodendrocytes (OLs) responded to oxidative injury by upregulating Serpina3n production and secretion. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells did not affect motor and cognitive functions in mice. Serpina3n depletion in Olig2-expressing cells did not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affect the population of other glial cells and neurons in vivo. In vitro primary cell culture showed that Serpina3n-sufficient and -deficient oligodendroglial progenitor cells (OPCs) differentiated into myelin gene-expressing OLs comparatively. Together, these data suggest that Serpina3n plays a minor role, if any, in regulating brain neural cell development and myelination under homeostatic conditions and raise interests in pursuing its functional significance in CNS diseases and injuries.