Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.