Viruses from diverse families, such as rabies virus, dengue virus, herpes simplex virus (HSV-1), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and cause multiple neurological manifestations, including headache, fever, loss of taste or smell, confusion and, in more severe cases, encephalitis, meningitis, and death. However, the underlying causes of neuropathology upon viral infection are still poorly understood. Our results revealed that SARS-CoV-2 and HSV-1 infection induces the fusion between neurons of mice and humans in primary cultures and brain organoids. We have discovered that this is caused by the presence of specialised viral surface molecules, fusogens, as this effect is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that fusion events are progressive, leading to the formation of multicellular syncytia, causing the spread of large molecules and organelles, and severely compromising neuronal activity. Our results provide mechanistic insights into how SARS-CoV-2, HSV-1 and other viruses might affect the nervous system, causing neuropathological symptoms.