In the context of the coronavirus disease 2019 (COVID-19) pandemic, Bacillus Calmette-Guérin (BCG), a tuberculosis (TB) vaccine, has been investigated for its potential to prevent COVID-19 with conflicting outcomes. Currently, over 50 clinical trials have been conducted to assess the effectiveness of BCG in preventing COVID-19, but the results have shown considerable variations. After scrutinizing the data, it was discovered that some trials had enrolled individuals with active TB, latent TB infection, or a history of TB. This finding raises concerns about the reliability and validity of the trial outcomes. In this study, we explore the potential consequences of including these participants in clinical trials, including impaired host immunity, immune exhaustion, and the potential masking of the BCG vaccine’s protective efficacy against COVID-19 by persistent mycobacterial infections. We also put forth several suggestions for future clinical trials. Our study underscores the criticality of excluding individuals with active or latent TB from clinical trials evaluating the efficacy of BCG in preventing COVID-19.