Herpes simplex encephalitis (HSE) is the most common infectious encephalitis, caused by lytic infection of the brain by herpes simplex virus (HSV)-1. We utilised a scalable iPSC system to study HSV-1 infection of human cortical neurones. HSV-1 completes its lytic replication cycle in these neurones within 30 hours, and neurone-to-neurone spread is observed. We profiled temporal changes to the neuronal transcriptome, cellular proteome, and cell-surface proteome during infection, revealing extensive modulation of host proteins involved in microtubule dynamics, signalling and trafficking. Notably, multiple families of voltage-gated ion channels are downregulated from the plasma membrane within 24 hours, accompanied by rapid loss of cellular trafficking protein GOPC. In peripheral cells, GOPC degradation is mediated by pUL56, a viral ubiquitin E3 ligase adaptor, and we confirm pUL56 also drives GOPC degradation in neurones. Using mutant viruses and genetically modified neurones we show that pUL56 is both necessary and sufficient for removal of the voltage-gated ion channels from the plasma membrane, but that ion channel removal is independent of GOPC expression. We demonstrate that pUL56 expression abolishes calcium signalling and neuronal electrical activity, both in isolation and during infection. There is growing evidence that HSV-1 exposure is linked to increased risk of Alzheimer’s disease, and our work defines a molecular mechanism by which transient or fulminant HSV-1 lytic infection could disrupt neuronal network activity. Our work also raises important safety questions regarding the use of HSV-1 as a gene delivery vector for targeting neurones.