Hongjam, derived from steamed and freeze-dried mature silkworm larvae, primarily consists (~70%) of silk peptides, notably sericin and fibroin. Previous studies have reported hepatoprotective properties of Hongjam via inhibition of phosphorylated AKT (p-AKT) signaling and angiogenesis. In this study, we evaluated the hepatoprotective effects of Hongjam using a methionine-choline deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) mouse model. Oral administration of Hongjam (0.01, 0.1, and 1 g/kg) or silymarin (0.1 g/kg, positive control) for eight weeks significantly improved liver histopathology, reduced hepatic injury markers (AST, ALT, ALP, total bilirubin, LDH), and dose-dependently decreased fibrosis markers (α-SMA, COL1A1, TIMP1). Additionally, Hongjam markedly downregulated hepatic expression of lipid uptake-associated genes (CD36, LPL, LDLR), surpassing the effects observed with silymarin, particularly on CD36 expression. To verify fibroin peptide as the key active hepatoprotective component, in vitro assays were performed in HepG2 cells treated with palmitic acid. Fibroin peptide treatment (GAGAGS, 50 and 100 µg/mL) significantly reduced intracellular lipid accumulation by elevating protein expression of p-AMPK, SIRT1, p-ACC, and PPARα, and reducing MCP1 levels. Collectively, these results confirm fibroin peptide as the primary bioactive constituent mediating Hongjam’s hepatoprotective and lipid-regulating effects, highlighting its therapeutic potential for liver fibrosis and related metabolic diseases.