We report a rare case of new-onset MDA-5-positive amyopathic dermatomyositis with rapidly progressive interstitial lung disease (RP-ILD) following the second dose of the COVID-19 mRNA vaccine. Our patient was a previously healthy Asian female in her 60 s who presented with fatigue, dyspnea on exertion, and typical dermatomyositis (DM) rashes without muscle involvement two weeks after receiving the second dose of the COVID-19 mRNA BNT162b2 vaccine. Workup revealed high titer MDA-5 antibodies, abnormal pulmonary function tests, and ground-glass opacities on chest imaging. She had good response to early aggressive therapy with high-dose steroids, intravenous (IV) rituximab, mycophenolate mofetil, and intravenous immunoglobulin (IVIG). This case highlights the potential immunogenicity of COVID-19 mRNA vaccines and the possibility of new-onset systemic rheumatic syndromes after vaccination. More studies are needed to understand a definitive causal relationship and improve surveillance of adverse immunological events following COVID-19 vaccinations.