This study systematically investigated the impact of ACE2 knockout (ACE2KO) on hepatic metabolic homeostasis and its molecular mechanisms, using integrated transcriptomic, proteomic, and metabolomic profiling. ACE2 deficiency exacerbates hepatic lipid accumulation, as evidenced by elevated total cholesterol and triglyceride levels, while disrupting the renin-angiotensin system equilibrium via increased angiotensin II (Ang II) and reduced Ang-(1-7). Histopathological analysis revealed hepatocyte edema, vacuolar degeneration, and inflammatory infiltration in the ACE2KO mice. Multi-omics integration uncovered systemic metabolic dysregulation: transcriptomics identified 1,004 differentially expressed genes (DEGs), including lipid metabolism regulators (Scd1, Fabp1) and circadian rhythm modulators (Arntl, Cry1), 191 differentially expressed proteins (DEPs) associated with interferon signaling activation (Oas1a, Rsad2) and lipid synthesis suppression (Scd1, Fasn), and metabolomics highlighted 193 differential metabolites (DEMs) indicative of bile acid dysregulation, glutathione redox imbalance, and amino acid metabolism anomalies. Cross-omics analysis indicated that the PPAR signaling pathway is a central regulatory hub driving lipid metabolic reprogramming and oxidative stress amplification. Furthermore, ACE2 deletion disrupted cytochrome P450-mediated detoxification and glutathione metabolism, thereby establishing a self-reinforcing oxidative injury cycle. These findings comprehensively delineate ACE2’s multifaceted role in hepatic metabolic homeostasis and provide mechanistic insights into and therapeutic targets for ACE2-associated liver diseases.