Background and Aim: Signs of dysautonomia were frequently observed in calves that died during foot-and-mouth disease (FMD) virus (FMDV) outbreaks in Egypt from 2015 to 2018. This study aimed to describe the clinical and histopathological features of the central nervous system in malignant cases of FMD and excluding possible concurrent bacterial, and bovine herpes virus 4 (BHV4) infections or both. Materials and Methods: In this study, 335 FMDV-infected buffalo calves aged 1-22 months were clinically examined and followed until recovery or death. Of the 335 calves, 134 died (malignant group) and 201 recovered after exhibiting classic symptoms of FMD (recover group). The calves were subjected to clinical examination. For the malignant group, several laboratory trials were conducted to assess the possible cause/s of dysautonomia-related viral, bacterial, or concurrent infections. Koch's postulates and polymerase chain reaction were employed. Postmortem and histopathological examinations of nervous tissue were performed. Results: In the malignant group, signs of dysautonomia were observed before death, including partial or complete gut dysfunction, loss of anal sphincter tone, rapid breathing sounds, fluctuating body temperature, and cardiac arrhythmias. In the malignant group, histopathological examination of the spinal cord, pons, medulla oblongata, hypothalamus, cerebellum, and cerebrum revealed demyelination, neuronal degeneration, and focal areas of malacia and gliosis. The nervous tissue and heart samples from malignant cases were positive for serotype O FMDV. Conclusion: Findings revealed in this study support the existence of neurodegeneration induced by FMDV infection in buffalo calves.