ApoE, a key regulator of lipid metabolism in the periphery, is the main apolipoprotein in the brain. In the brain, ApoE has been shown to regulate several pathways that impact the development, function, and plasticity of neuronal synapses and, as a result, exerts large influence over brain synaptic dynamics. These pathways include the regulation of the transport, from astrocytes to neurons, of cholesterol, a unique membrane lipid with critical functions in the processes of synaptic formation, function, and plasticity. Notably, in this pathway, cholesterol metabolites that regulate plasticity in neurons have been found to also signal back to astrocytes in coordination of astrocytic cholesterol metabolism. These ApoE pathways also include the regulation of cytokine expression by brain glial cells, through which ApoE may impact several forms of synaptic plasticity including homeostatic and competitive synaptic plasticity. Furthermore, ApoE has been found to directly modulate the oligomerization dynamics of amyloid β peptides and, as a result, may further regulate homeostatic, competitive, and other forms of synaptic plasticity in the brain via amyloid β. Thus, ApoE plays a multifaceted role in the brain in the regulation of synaptic development, function, and plasticity.