Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked heterogeneity and sex differences, yet the molecular mechanisms underlying disease progression remain incompletely understood. Here, we present the largest integrative multi-omics study to date combining matched liver tissue and blood profiling in 211 biopsy-confirmed, morbidly obese individuals with MASLD undergoing bariatric surgery. We integrate hepatic transcriptomics, metabolomics, and lipidomics with serum metabolomics to resolve compartment-specific and sex-dependent molecular networks. Across sexes, MASLD is characterized by suppressed hepatic amino acid metabolism and extensive lipid remodeling, accompanied by inverse metabolic signatures in circulation, consistent with systemic spillover. Strikingly, disease progression in men is driven by a streamlined triacylglycerol-centric pathway that mediates transcriptional effects on steatosis and inflammation, whereas women exhibit distributed, multi-layered networks linking lipid, amino acid, and immune pathways. Mediation analyses identify hepatic lipid modules as key intermediates connecting gene expression to histopathology. These findings reveal sex-specific molecular architectures of MASLD, demonstrate that circulating biomarkers do not reflect hepatic metabolism, and provide a framework for sex-specific precision medicine.