Systemic distribution of viral pathogens often requires the interaction of viruses with cells of the vascular system, of which endothelial cells are an indispensable part. One such virus is the Herpes simplex virus type 1 (HSV-1). HSV-1 is a highly contagious ubiquitous pathogen, which commonly causes blisters or cold sores, but may play an important role in the development of Alzheimer's disease, severe septic processes as well as atherosclerosis. Since no virus-specific vaccine is available to prevent HSV-1 infections, the identification of host cell proteins, which are involved in HSV-1 replication, and the modulation of their activity might be a promising aim to develop future antiviral therapies and one such candidate could be AMP-activated protein kinase (AMPK), known to be the master regulator of cellular pathways. To gain insights into the role of AMPK in HSV-1 replication, human umbilical vein endothelial cells were infected with HSV-1 and alterations caused by this infection were examined. Our data demonstrated that HSV-1 replicates in endothelial cells and HSV-1 infection led to alteration of various signaling pathways. The Akt/mTORC1 pathway is important for viral replication. We showed that HSV-1 replication is controlled by AMPK, an increase in viral concentration is observed in AMPK knockdown and knockout cells and, on the other hand, a decrease in viral concentrations is seen in cells treated with AMPK activators. Our results lead us to direct the protective role of AMPK through metabolic pathways. AMPK activation inhibits fatty acid synthesis and cholesterol biosynthesis and this could be the mechanism for its antiviral role in endothelial cells. Our data indicates a protective role of AMPK against HSV-1 replication in endothelial cells via inhibition of metabolic pathways. This data could pave way for developing antiviral strategies using AMPK, a host cell protein which, according to the current global situation is a need of the hour.