Anti-IgLON5 disease is an autoimmunity/neurodegeneration overlap disorder, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction. Whether neuronal Tau protein pathology and neurodegeneration found in the patient’s brains are directly related to anti-IgLON5 AABs remains unclear. We find that patient-derived anti-IgLON5 AABs induce the clustering of cell surface IgLON5 with other proteins, leading to acute neuronal hyperactivity that triggers pro-pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wildtype mice, anti-IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. These findings provide first direct evidence that anti-IgLON5 AABs are causally linked to Tau pathology in anti-IgLON5 disease patients, thereby providing important new insights into the disease mechanisms, and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology.