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Sepsis-induced acute liver injury (SALI) is a severe complication with high mortality, largely driven by excessive reactive oxygen species (ROS) and uncontrolled inflammation. The heart is also frequently affected in sepsis, manifesting as cardiomyopathy and arrhythmias. Sepsis can also precipitate heart failure and myocardial infarction. However, targeted therapies that simultaneously address oxidative stress and inflammatory organ damage remain lacking. Tanshinone IIA (Tan) exhibits potent antioxidant and anti-inflammatory activities, but its poor water solubility and low bioavailability limit clinical translation. Herein, we develop a mannosamine-modified PLGA-PEG nanoparticle encapsulating tanshinone IIA (Tan-NPs) via a double-emulsion solvent evaporation method for targeted delivery to liver macrophages. The nanoparticles display uniform spherical morphology (105.3 nm), narrow size distribution (PDI < 0.2), favorable negative zeta potential, and excellent colloidal stability in physiological media. Tan-NPs achieve efficient lysosomal escape, potently scavenge intracellular ROS, restore mitochondrial membrane potential, and reduce apoptosis in LPS-stimulated RAW264.7 macrophages. They significantly suppress the secretion of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and shift macrophage polarization from the M1 to the anti-inflammatory M2 phenotype. Following intravenous injection into mice with LPS-induced sepsis-associated acute liver injury, Tan-NPs preferentially accumulate in the liver via mannose receptor-mediated active targeting, dramatically ameliorate hepatic histopathological damage, and reduce both oxidative stress and NF-κB activation. Importantly, the nanoparticles exhibit excellent biocompatibility with no overt cytotoxicity or hemolysis. Collectively, Tan-NPs show potential as a targeted nanomedicine for the treatment of sepsis-induced acute liver injury, with potential applicability to other ROS-driven inflammatory diseases.