We herein report a case involving a patient with quiescent ulcerative colitis (UC) in long-term clinical remission whose condition rapidly worsened after receiving a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, leading to colectomy due to toxic megacolon. The patient received the fifth dose of the Spikevax (mRNA-1273) vaccine and experienced a severe flare-up of UC 6 days later. Pathologic findings of the surgical specimens were consistent with severe active UC concomitant with cytomegalovirus infection. Because mRNA vaccines stimulate both humoral and cellular immunogenicity, it is important to note that they can be a triggering factor for the relapse of UC.