Sepsis is known since the time (470 BC) of great Greek physician, Hippocrates. Advancement in modern medicine and establishment of separate branches of medical science dealing with sepsis research have improved its outcome. However, mortality associated with sepsis still remains higher (25–30%) that further increases to 40–50% in the presence of septic shock. For example, sepsis-associated deaths account more in comparison to deaths-associated with myocardial-infarction and certain cancers (i.e. breast and colorectal cancer). However, it is now well established that profound activation of innate immune cells including macrophages play a very important role in the immunopathogenesis of sepsis. Macrophages are sentinel cells of the innate immune system with their location varying from peripheral blood to various target organs including lungs, liver, brain, kidneys, skin, testes, vascular endothelium etc. Thus, profound and dysregulated activation of these cells during sepsis can directly impact the outcome of sepsis. However, the emergence of the concept of immunometabolism as a major controller of immune response has raised a new hope for identifying new targets for immunomodulatory therapeutic approaches. Thus this present review starts with an introduction of sepsis as a major medical problem worldwide and signifies the role of dysregulated innate immune response including macrophages in its immunopathogenesis. Thereafter, subsequent sections describe changes in immunometabolic stage of macrophages (both M1 and M2) during sepsis. The article ends with the discussion of novel macrophage-specific therapeutic targets targeting their immunometabolism during sepsis and epigenetic regulation of macrophage immunometabolism and vice versa.