In the era of the COVID-19 pandemic declared in March 2020, widespread vaccination protocols were initiated to mitigate the severity and spread of COVID-19. Although COVID-19 vaccines have been generally considered safe, adverse events post-vaccination have been reported, including the development of demyelinating disease. We report a rare case of de novo aquaporin-4-positive neuromyelitis optica spectrum disorder (NMOSD) in an 80-year-old man following BNT162b SARS-CoV-2 vaccination to raise the awareness of this possible severe adverse event in an older adult. An 80-year-old South Asian man presented 2 days following his second dose of the Pfizer-BioNTech COVID-19 mRNA BNT162b2 vaccine with progressive left-sided leg weakness and numbness resulting in falls. MRI of the spine revealed a longitudinally extensive transverse myelitis from T3-T4 to T9-T10. Serum antibody testing revealed positive aquaporin-4 (AQP4) antibodies. He was diagnosed with AQP4-positive NMOSD and was treated with high-dose intravenous methylprednisolone and plasma exchange with some improvement. He was subsequently treated with mycophenolate mofetil and a slow steroid wean. This case report adds to the existing literature and suggests that COVID-19 vaccinations may trigger de novo NMOSD or NMOSD relapses in some individuals. Although rare, our patient presented with new-onset NMOSD in his 80 s following COVID-19 vaccination. As such, it is relevant to consider AQP4 testing in those presenting with a post-vaccination myelitis, regardless of age. Ongoing vaccine surveillance and research are needed to understand the risk of NMOSD post-COVID-19 vaccinations further.