Kim et al. (2016) found that mitophagy could be induced to inhibit NLRP3 (NLR family pyrin domain containing 3) activation in macrophages to suppress sepsis; however, Patoli et al. (2020) indicated that inhibition of mitophagy powers macrophage activation and defense against bacterial action during sepsis. In this review, we summarize the detailed mechanisms of mitophagy (Figure 1) in mammalian cells as well as its protective role in septic organ dysfunction as underlying therapeutic targets for sepsis. The gene discussed is NLRP3; the disease is Sepsis.