Mycobacterium leprae causes leprosy. M. leprae enters the body through the upper respiratory tract where it interacts with host’s cells. Interferon (IFN) is a class of cytokines in human body that are released in case of viral and intracellular pathogen infection and they activate the immune cells to eradicate those pathogens. IFN-γ (Type-II IFN) confers immunity against bacterial, viral, and protozoan diseases. Loss of function mutations in IFN-γ results in poor immunity towards mildly virulent mycobacterium. Upon M. leprae invasion, monocytes enter the site of infection and differentiates into macrophages. IFN-γ induces endothelial cells (EC) of the pathogenic micro-environment to cause monocyte differentiation into pro-inflammatory M1 macrophages for immediate antimicrobial activity. This differentiation is ceased in the absence of endothelial cells. M1 macrophages are clinically more active than anti-inflammatory M2 macrophages induced by resting EC. The former produced higher amounts of pro-inflammatory cytokines in response to the TLR2/1 ligand of M. leprae. The former also showed elevation of vitamin D-associated antimicrobial pathway genes, which are required to counter M. leprae. In addition, the former accumulates less oxidised LDL to prevent growth of M. leprae. Thus, advancement of IFN-γ research would help in the design of next-generation anti- leprosy therapeutics.