Human apolipoprotein E (ApoE) has been shown to play important roles during primary infection and pathogenesis of several viruses. Furthermore, epidemiological studies suggest that interactions between ApoE 4 and herpes simplex virus type-1 (HSV1) could associate with higher risk of Alzheimer’s disease. Nevertheless, little is known about the ApoE-HSV1 interactions at molecular levels. Here, we investigate the effects of ApoE on HSV1 infection in vitro. Our results show that ApoE promotes HSV1 growth, which is attributed to the incorporation of ApoE into HSV1 particles. Using both biological and biophysical approaches, we conclude that ApoE-coated HSV1 demonstrates a more efficient attachment to and faster release from the cell surface. Mechanistic studies reveal that ApoE modifies HSV1 interactions with heparan sulfate, thereby modulating interactions between HSV1 and the cell surface. Overall, our results provide new insights into the roles of ApoE during HSV1 infections which may inspire future studies on Alzheimer’s disease etiology.