Glial cells play a critical role in the healthy and diseased phases of the central nervous system (CNS). CNS diseases involve a wide range of pathological conditions characterized by poor recovery of neuronal function. Glial cell-related target therapies are progressively gaining interest in inhibiting secondary injury-related death. Modulation of the extracellular matrix by artificial scaffolds plays a critical role in the behavior of glial cells after injury. Among numerous types of scaffolds, self-assembling peptides (SAPs) notably give attention to the design of a proper biophysical and biomechanical microenvironment for cellular homeostasis and tissue regeneration. Implementing SAPs in an injured brain can induce neural differentiation in transplanted stem cells, reducing inflammation and inhibiting glial scar formation. In this review, we investigate the recent findings to elucidate the pivotal role of SAPs in orchestrating the most pivotal secondary response following CNS injury. Notably, we explore their impact on the activation of glial cells and their modulatory effects on microglial and astrocytic polarization.