Abstract： Coronavirus Disease 2019 (COVID-19) is caused by 2019 novel coronavirus (2019-nCoV). Type I and type III interferons, as important available clinically used broad-spectrum antiviral drugs, have been considered as promising candidate drugs for the treatment and prevention of COVID-19. In early 2020, more than 40 clinical trials, including the World Health Organization (WHO) SOLIDARITY study, have been launched in the world to explore the clinical efficacy and application method of interferons in the treatment of COVID-19. Meanwhile, animal models and human clinical specimens were used in many laboratories to explore the immunologic role and mechanistic function of interferons in COVID-19. However, the conclusion of the studies in the past three years were not consistent and even contradictory albeit numerous data were accumulated by the scientific community, which reflects the complexity of the role and function of interferons in COVID-19. Recently, the results of four large high-quality randomized controlled phase III clinical trials were reported. In this review, we systematically summarize and analyze the complicated and contradictory data from the level of immunopathological mechanism and clinical trials. We clarify that the heterogeneous clinical outcome of 2019-nCoV infection is closely related to the level and production time of interferons and that interferons are protective in the early stage of COVID-19 but may cause immunological damages in the late stage which may exacerbate inflammation. Further high-quality prospective clinical trials that strictly control confounding factors are still warranted to finally elucidate the precise role and clinical application of interferons in COVID-19.