Background: The COVID-19 pandemic resulted in significant mortality and morbidity globally. The introduction of various COVID-19 vaccines at record time generated hope among people and doubts and apprehension regarding their safety. The study was done to estimate the incidence of COVID-19 vaccine breakthrough infections among Health Care Workers working in a tertiary care hospital and evaluate the outcome of these infections. Methods: A prospective Cohort study was conducted among 6342 healthcare workers in a tertiary care hospital having received at least one dose of any COVID-19 vaccine. They were followed up for COVID-19 vaccine breakthrough infection for one year by epidemiological investigations. Data on COVID-19-positive healthcare workers was obtained through personal interviews and case records. Results: 490 (7.9%) developed COVID-19 vaccine breakthrough infection during the study period. The majority of them (96.7%) were asymptomatic, and 16 (3.3%) of them developed complications needing hospitalization with 2 deaths. A statistically significant association was found in sex, healthcare worker categories, co-morbidities, and Blood groups. Conclusion: COVID-19 vaccination among healthcare workers reduces the incidence, severity, and complications of COVID-19 vaccine breakthrough infections. The risk of acquiring COVID-19 vaccine breakthrough infections was higher among males, partially vaccinated individuals, people with co-morbidities, and those involved in the regular care of COVID-19 patients. COVID-19-appropriate behaviour and receiving all the primary doses of vaccine will be instrumental in COVID-19 control.