Abstract Innate immune response is pivotal for host defense against pathogenic infections. It is, however, often ineffective to provide protection against infections and fails to efficiently respond to the existing conditions. Induction of host response or direct targeting of the invading pathogens then becomes desirable to reduce the disease progression. Activation of HO-1 by a natural substrate hemin effectively enhanced the ability of human macrophage to resist infections by several pathogens, including HIV-1, dengue virus, West Nile virus, poxvirus, and Leishmania donovani. HO-1 expression in a prostate cancer cell line susceptible to infection by XMRV resulted in substantial reduction in virus production by infected cells. Reduction of intracellular pathogens in HO-1-activated cells was attenuated by pretreatment of cells with SnPP IX, a specific inhibitor of HO-1 activity, indicating a key role of this endogenous enzyme in the host defense mechanism. Considering effective treatment of these infections is a continuous daunting challenge due to the emergence of drug resistant mutants, unlocking of HO-1-dependent regulatory genes may provide novel biomarkers and therapeutic targets for treating multiple infections and disease conditions.