Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccination is essential for controlling the outbreak and preventing severe disease. However, there are still uncertainties about the safety of COVID-19 vaccination in individuals with chronic liver disease. Case Presentation: Three patients with hepatitis B virus (HBV) infection presented to our hospital with acute-on-chronic liver failure (ACLF) due to HBV flare after COVID-19 vaccination (mRNA-1273 and ChAdOx1 nCoV-19). Their COVID-19 antibodies were tested by Elecsys Anti-SARS-CoV-2 S immunoassay, which showed good response after full two-dose course of vaccine. One patient refused the test. The patients’ clinical conditions deteriorated during hospitalization. Patient 1 received Entecavir (Baraclude) 1 mg/day upon presentation, but the serum bilirubin level and international normalized ratio (INR) kept increasing. He was comatose in one week and underwent urgent living donor liver transplantation. Patient 2 was on regular Entecavir (Baraclude) 0.5 mg/day and was increased to 1 mg/day upon admission. The serum bilirubin level and INR kept increasing, and he developed grade 3 hepatic encephalopathy in three weeks. The patient then received urgent living donor liver transplantation. Patient 3 received Entecavir (Baraclude) 1 mg/day upon presentation. Her serum bilirubin and INR kept increasing, and her mental status altered in a week. She did not undergo liver transplantation for her old age. Conclusions: It is not still unclear whether there is a cause-and-effect relationship between COVID-19 vaccination and HBV infection flare. Furthermore, the mechanism of COVID-19 vaccine-induced HBV reactivation is not established. Further studies are needed in this regard. However, during the COVID-19 pandemic, prophylactic antiviral therapy for HBV infection before COVID-19 vaccination should be considered.