In central nervous system (CNS), demyelination is a pathological process featured with a loss of myelin sheaths around axons, which is responsible for the diseases of multiple sclerosis, neuromyelitis optica, and so on. Transforming growth factor-beta1 (TGF-beta 1) is a multifunctional cytokine participating in abundant physiological and pathological processes in CNS. However, the effects of TGF-beta 1 on CNS demyelinating disease and its underlying mechanisms are controversial and not well understood. Herein, we evaluated the protective potential of TGF-beta 1 in a rodent demyelinating model established by lysophosphatidylcholine (LPC) injection. It was identified that supplement of TGF-beta 1 evidently rescued the cognitive deficit and motor dysfunction in LPC modeling mice assessed by novel object recognition and balance beam behavioral tests. Besides, quantified by luxol fast blue staining, immunofluorescence, and western blot, administration of TGF-beta 1 was found to significantly ameliorate the demyelinating lesion and reactive astrogliosis by suppressing p38 MAPK pathway. Mechanistically, the results of in vitro experiments indicated that treatment of TGF-beta 1 could directly promote the differentiation and migration of cultured oligodendrocytes. Our study revealed that modulating TGF-beta 1 activity might serve as a promising and innovative therapeutic strategy in CNS demyelinating diseases.