Sepsis, caused by the inappropriate host response to infection, is characterized by excessive inflammation response and organ dysfunction, continues to be a critical clinical problem. Commonly, sepsis may progress to septic shock and have a high risk of complications, including acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), sepsis-induced myocardial dysfunction (SIMD), liver dysfunction, cerebral dysfunction, and skeletal muscle atrophy, predominantly contributing to high mortality. Additionally, viral sepsis may be critical for the pathogenesis of coronavirus disease 2019 (COVID-19). Renin-angiotensin system (RAS) may represent as an effective therapeutic target for sepsis therapies. The role of RAS involved in the pathogenesis of sepsis has been spotlighted and some preclinical and clinical trials studies targeted at RAS for sepsis treatment have shown promising results. Herein, we attempt to review the effects and mechanisms of RAS manipulation on sepsis and provide new insights into optimization RAS modulation for this terrible heterogeneous syndrome.