In this study, we investigated the effects of HSV-1 infection on tau phosphorylation in human brain cortical organoids. Our findings demonstrate that HSV-1 triggers nuclear accumulation of phosphorylated tau in neurons within the developing cortical plate as well as in neural precursor cells (NPCs) in the ventricular/subventricular-like zones of these differentiating cortical structures. Antiviral treatment effectively inhibited nuclear tau accumulation in both KOS- and 17syn+-infected organoids. Importantly, for the first time we provide evidence of a potential interaction of phosphorylated tau with HSV-1 genome. Furthermore, we ruled out the involvement of the Cyclin-dependent kinase 5 (Cdk5) in the nuclear phosphorylation of tau. Finally, we show that HSV-1 causes a significant alteration in the abundance of components of nuclear speckles and proteins known to be associated with neurodegenerative diseases.