<p>Sepsis is defined as a critical multi-organ dysfunctional condition accompanied by hyper-inflammatory and immunosuppressive states. Immune cells are the vital players in modulating this fatal condition. Macrophages have long been known to impart modulatory effects during the initiation as well as progression of sepsis. They are highly plastic in nature and their high abundance in different organs renders them potential candidates for detailed investigation. Macrophages can be regarded as key therapeutic targets as they are less prone to apoptotic cell death when compared to other immune cells like dendritic cells or lymphocytes. The pathogens that cause infectious diseases are not solely responsible for macrophage polarization, cytokine expression, and their modulation, but recent studies have highlighted internal mechanisms of macrophages such as various metabolic pathways, and autophagic activities to be crucial in regulating themselves during different stages of sepsis. Considering their vitality, methodologies such as macrophage-based immunotherapy and usage of nanoparticles have emerged as promising therapeutic approaches. In this review, we summarize different aspects of macrophages in a holistic way for better understanding and provide more concise knowledge of how macrophages interact during sepsis pathogenesis, and how they can be modulated and targeted for making further advancements in therapeutic research.</p>