Neurotropic viruses can alter neuronal responses in the central nervous system (CNS), significantly affecting viral clearance and disease progression. Herpes simplex virus type 1 (HSV-1) brain infection may lead to life-threatening severe acute encephalitis in untreated patients and neurological sequelae in survivors despite antiviral treatment. Notably, asymptomatic brain infection occurs in an important proportion of healthy individuals (>35%) and is associated with residual chronic neuroinflammatory responses that may lead to neurodegeneration. Therefore, understanding the molecular basis of these detrimental effects and finding and advancing new therapeutic strategies to manage HSV-1 brain infections are needed. Neuropeptides are pleiotropic neuroimmune mediators expressed throughout the CNS that modulate glial activation, cytokine production, and neuronal survival. However, their regulation during HSV-1 brain infections remains largely unexplored. Here, we sought to investigate the expression dynamics of two neuropeptides, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP), in two mouse strains that model human traits of symptomatic and asymptomatic HSV-1 brain infections (BALB/c and C57BL/6, respectively), as well as in the human neuroblastoma cell line SH-SY5Y, to uncover potential differences that could help explain the susceptibility of some individuals to develop severe HSV-1 infection. Our findings provide evidence that HSV-1 brain infection modulates NPY and VIP mRNA expression in a neurovirulence- and host-susceptibility-dependent manner, which may be associated with disease severity and chronic damage, warranting further evaluation.