Liver fibrosis is a major complication of chronic liver injury, driven in part by Signal Transducer and Activator of Transcription 1 (Stat1). This study evaluated passively liver targeted polymeric nanocarriers delivering Stat1 siRNA (si-STAT1) to treat steatohepatitis and fibrosis in a thioacetamide (TAA) mouse model. Two polyplex nanocarriers with different core−corona ratios, EN15 and EN76, were tested in TAA-treated mice and activated human and murine hepatocytes. In vitro, both formulations enabled efficient cellular uptake and Stat1 silencing, reducing TAA-induced lipid accumulation. Through an In vivo approach, mice received TAA for 16 weeks followed by four weeks of siSTAT1 treatment. Both formulations reduced collagen deposition, hepatic inflammation, and fibrosis scores. Notably, EN76, which preferentially targets non-parenchymal cells, showed superior antifibrotic efficacy compared with EN15. These findings highlight Stat1 as a key driver of steatohepatitis and fibrosis and support passive siRNA delivery, particularly via EN76, as a promising therapeutic strategy.