In multiple sclerosis efficiency of remyelination declines with progression of the disease. It remains not fully understood how the changes in the biomechanical and biochemical microenvironment of demyelinating lesions contribute to decreased remyelination. Here, we show that the mechanical changes of the extracellular materials and the extracellular acidic pH, both characteristic features of demyelinating lesions, affect key biological processes involved in the response of oligodendrocyte precursor cells (OPCs) to myelin loss. Specifically, we show that OPC survival, proliferation, migration, and differentiation into adult oligodendrocytes (OLs) in vitro depend on the mechanical stiffness of polymer hydrogels representing the range of brain tissue stiffness, and that these processes decrease on more compliant gels. Further, we show that the brain tissue becomes more compliant after demyelination, creating mechanically unfavorable environment for OPCs. Separately, we show that OPC migration, survival, proliferation, and differentiation decrease in acidic extracellular pH, and that OPCs migrate toward acidic pH in pH gradients representative of the interface between healthy tissue and acidic brain lesions. As these processes are integral to OPC response to axon demyelination, our results suggest that changed mechanical properties and acidity of demyelinating lesion could contribute to decreased remyelination.