PUFA of then-3 andn-6 families are present in high concentration in the brain where they are major components of cell membranes. The main forms found in the brain are DHA (22 :6,n-3) and arachidonic acid (20:4,n-6). In the past century, several studies pinpointed that modifications ofn-3 andn-6 PUFA levels in the brain through dietary supply or genetic means are linked to the alterations of synaptic function. Yet, synaptopathies emerge as a common characteristic of neurodevelopmental disorders, neuropsychiatric diseases and some neurodegenerative diseases. Understanding the mechanisms of action underlying the activity of PUFA at the level of synapses is thus of high interest. In this frame, dietary supplementation in PUFA aiming at restoring or promoting the optimal function of synapses appears as a promising strategy to treat synaptopathies. This paper reviews the link between dietary PUFA, synapse formation and the role of PUFA and their metabolites in synaptic functions.