Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for the prevention of tuberculosis. In addition to tuberculosis, BCG has a non-specific protective effect on the prevention of non-homologous pathogens such as bacteria, viruses, parasites and so on. It is also used for immunotherapy of some tumors and autoimmune diseases. The non-specific protective mechanism of BCG is identified to be related to the induction of trained immunity. The mechanisms of BCG-induced trained immunity involve cell metabolism changes in host innate immune, epigenetic reprogramming, and enhanced immune responses to restimulation. BCG-induced trained immunity provides protective effects against multiple viral infections and is negatively associated with the mortality of coronavirus disease 2019 (COVID-19), which may have the impact on emerging pathogen pandemic in the future.