Sepsis is characterized by a dysregulated host response to infection; this can lead to multiorgan dysfunction where liver and kidneys play a key role. This study evaluated whether long-term oral administration of A12C modulates hepatic and renal homeostasis under basal conditions and during polymicrobial sepsis. Forty-five male Sprague–Dawley rats were allocated to healthy control (SAN), healthy A12C-treated (STO), septic control (IC), or septic A12C-treated (IA) groups. A12C was administered in drinking water at 6×10⁸ CFU/mL for 30 days, and sepsis was induced by caecal ligation and puncture (CLP). Gene expression, protein abundance, antioxidant enzyme activities, and histopathological alterations were evaluated in liver and kidney. Under basal conditions, A12C reduced hepatic Tlr4 and Tgfb1 expression and TLR4, ICAM-1, and SOD2 protein abundance, whereas renal Tnf and Icam1 expression and SOD and GRd activities increased. During sepsis, A12C-treated rats showed lower hepatic expression of Tnf, Il6, Ccl2, Icam1, and Nos2, together with increased SOD1 protein abundance. In kidney, A12C reduced Tlr4, Il6 and Icam1 expression and increase CAT, GPx, and GRd activities. Reduced expression of several inflammatory and endothelial mediators was detected in both organs and a marked enhancement of renal antioxidant defences during sepsis. The present results support the potential of A12C to improve the host response to sepsis and limit sepsis-associated organ dysfunction, possibly through a preconditioning-like mechanism.