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Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for Alzheimer’s disease (AD). Viral infection of neuronal cells can reproduce hallmark pathological features of AD, including intracellular beta-amyloid (Aβ) accumulation, tau hyperphosphorylation, and lysosomal dysfunction. However, the molecular mechanisms underlying these alterations remain unclear, partly due to limitations of existing experimental models. Here, we established both two-dimensional (2D) and three-dimensional (3D) LUHMES neuronal cultures—a human mesencephalic-derived neural cell line that differentiates rapidly into mature neurons—to investigate HSV-1-induced neurodegeneration. Our results demonstrate that HSV-1 infection induces key features of AD, including intracellular accumulation of Aβ peptides and hyperphosphorylation of tau protein. Moreover, we observed significant disruptions in the autophagy-lysosome pathway, characterized by increased LC3-II levels, reduced cathepsin activity, and impaired lysosomal burden. Notably, these AD-like alterations were reproduced in 3D LUHMES neuronal aggregates, confirming their susceptibility to productive HSV-1 infection. Collectively, these findings indicate that HSV-1 not only triggers classical AD-like neuropathological markers but also disrupts cellular clearance mechanisms that may contribute to neuronal dysfunction and degeneration. This study validates the 3D LUHMES system as a physiologically relevant human neuronal model to study virus-induced neurodegeneration and its mechanistic links to AD pathology.