This systematic review evaluates the efficacy and safety of COVID-19 vaccines in individuals with cystic fibrosis (CF). A systematic search of major databases conducted between December 2019 and January 2024 identified eight cohort studies comprising 1,361 CF patients. Studies without subgroup analyses specific to CF patients were excluded, which may have limited the generalizability of findings, particularly for CF lung transplant recipients. COVID-19 vaccines generally induced robust serological responses following the second and third doses, although reduced antibody levels were observed in lung transplant recipients. Factors influencing humoral response included prior SARS-CoV-2 infection, age, inhaled corticosteroid use, and immunosuppressive therapy. Vaccination-related adverse events were predominantly mild. Although breakthrough infections were reported, severe COVID-19 outcomes were infrequent among vaccinated CF patients. The evidence supports the immunogenicity and safety of COVID-19 vaccines in the CF patients. However, individualized vaccination strategies may be necessary for CF lung transplant recipients and those on immunosuppressive therapies. Further research is essential to optimize vaccination strategies and to identify risk factors associated with breakthrough infections in this high-risk population.