The regulation of synaptic plasticity is closely related to the activity of the ionotropic glutamate receptor. Postsynaptic density protein 95 （PSD-95） is a postsynaptic scaffold protein. It plays a very important role in maintaining the stability of ionotropic glutamate receptors， such as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor （AMPAR） and N-methyl-D-aspartate receptor （NMDAR）， at the postsynaptic membrane. In recent years， the interaction between palmitoylation of PSD-95 and ionotropic glutamate receptors （AMPAR and NMDAR） has also attracted extensive attention. This review focuses on the palmitoylation process of PSD-95 and ionotropic glutamate receptors （AMPAR and NMDAR）， as well as the research progress of the above palmitoylation process in epilepsy， Alzheimer’s disease， Huntington’s disease， and neuronal ceroid lipofuscinosis， so as to provide new research ideas for the treatment of central nervous system diseases.