Background: Intravesical Bacille Calmette–Guérin (BCG) therapy is a widely adopted treatment for non-muscle-invasive bladder cancer (NMIBC). Despite its extensive use, the historical origins of BCG therapy remain under-appreciated by many practitioners. Initially developed as a tuberculosis vaccine by Albert Calmette and Camille Guérin in the early 20th century, BCG’s immunomodulatory potential was later harnessed for cancer treatment. The unintended discovery of its attenuated virulence, combined with extensive subsequent research, laid the foundation for its clinical application in bladder cancer. Currently, BCG is a cornerstone treatment for NMIBC, particularly in high-risk cases, and has significantly influenced the evolution of modern immunotherapies, including checkpoint inhibitors. Objective: This paper was written with the intent of exploring the origins of BCG and historically significant research that led to it’s use and acceptance as a treatment for NMIBC while highlighting it’s impact on the development of immunotherapy as a whole. Conclusion: The BCG vaccine’s journey from a tuberculosis preventive to a groundbreaking cancer treatment underscores the interconnected nature of scientific discovery and its enduring impact on modern medicine.