Sepsis is defined as the dysregulated immune response leading to multi-organ dysfunction and injury. Sepsis-induced acute kidney injury is a significant contributor to morbidity and mortality. Alamandine (ALA) is a novel endogenous peptide of the renin-angiotensin-aldosterone system. It is known for its anti-inflammatory and anti-apoptotic effects, but its functional and vascular effects on sepsis remain unclear. We aimed to investigate the effects of ALA, as a pre- and post-treatment agent, on lipopolysaccharide (LPS)-induced systemic and renal dysfunction and injury in the LPS-induced endotoxemia model in rats via functional, hemodynamic, vascular, molecular, biochemical, and histopathological evaluation. 10 mg/kg intraperitoneal LPS injection caused both hepatic and renal injury, decreased blood flow in several organs, and renal dysfunction at 20 h in Sprague-Dawley rats. Our results showed that ALA treatment ameliorated systemic and renal inflammation, reduced inflammatory cytokines, prevented the enhancement of the mortality rate, reversed vascular dysfunction, corrected decreased blood flows in several organs, and reduced renal and hepatic injury via inhibiting iNOS (inducible nitric oxide synthase) and caspase expressions in the kidney. In addition, expressions of different ALA-related receptors showed alterations in this model, and ALA treatment reversed these alterations. These data suggest that ALA's systemic and renal protective effects are achieved through its anti-inflammatory, anti-pyroptotic, and anti-apoptotic effects on hemodynamic and vascular functions via reduced iNOS expression.