The vaccines developed to prevent infection and mitigate morbidity and mortality in patients with COVID-19 demonstrated high efficacy in clinical trials but were associated with adverse events, most of which were mild and transient. However, some adverse events were rather serious, with grave prognoses. Of note, a few cases of autoimmune hematological conditions such as thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), and vaccine-induced immune thrombotic thrombocytopenia (VITT) were reported. TTP following Pfizer-BioNTech mRNA vaccination is exceptionally rare, with very scant literature. This case report describes an interesting case of a 61-year-old woman who presented 22 days after receiving the third dose of the Pfizer-BioNTech mRNA COVID-19 vaccine with malaise, bloody stools, and jaundice. Her medical history was significant for multiple myeloma previously treated with autologous bone marrow transplant and in remission with chemotherapy. She also had a history of chronic heart failure with preserved ejection fraction (HFpEF) and neuropathy treated with daily vitamins. The diagnosis was predicted by her classic presentation and was clinched by low ADAMTS13 activity. She was treated with plasmapheresis, steroids, and monoclonal antibodies. Intriguingly, her hospital stay was further complicated by an episode of generalized tonic-clonic seizure requiring intubation and mechanical ventilation for airway protection. Albeit infrequent, COVID-19 vaccine-associated TTP is associated with substantial morbidity and mortality. Hence, early diagnosis and treatment are essential in patients presenting with thrombocytopenia after COVID-19 vaccination.