An increasing amount of evidence reveals that an orchestrated interplay between myeloid subpopulations in the hematopoietic system plays a significant role in supporting normal functions of the immune system and facilitating homeostatic restoration upon exogenous or endogenous insults. Heme oxygenase-1 (HO-1), a microsomal enzyme discovered decades ago, can metabolize pro-oxidant heme into biliverdin, free iron, and carbon monoxide. This enzymatic reaction produces biological materials, contributing to major immunomodulatory effects. Specifically, HO-1 expression in myeloid cells has been generally acknowledged to drive potent anti-inflammatory and immunosuppressive responses. In this review, the authors focused on elucidating the potential mechanisms underlying myeloid HO-mediated immunomodulation phenotypes, and discussed the potential application of myeloid-specific HO-1 induction as an anti-inflammation therapeutic strategy.