Abstract Body: Atherosclerotic cardiovascular disease (ASCVD) is the primary cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). Currently, no treatments target both conditions simultaneously, partly due to the scarcity of animal models that reflect both diseases, especially in females. Male and female Ldlr^-/- mice (n=8-13) were fed various diets—including a Western diet (WD), a modified choline-deficient high-fat diet (mCDHFD), or a modified MASH-inducing diet (mMASHD)—containing equivalent cholesterol levels. Using comprehensive multiomics—metabolomics, lipidomics, and transcriptomics—combined with histopathology and biochemical analyses, we characterized the coexistence of MASH and atherosclerosis. Transcriptomics findings were validated across other mouse models and integrated with human data (n=79). While mCDHFD caused MASH fibrosis in both sexes, WD was effective only in males, whereas mMASHD mainly affected females. The mCDHFD promoted both MASH and atherosclerosis concurrently in both sexes, but WD only mimicked disease co-occurrence in males. Correlation analysis indicated a link between MASH and atherosclerosis, identifying circulating cholesterol and CCL2 as potential predictors of dual disease (p<0.04). Metabolomics combined with transcriptomics pinpointed pathways—arginine-proline, glycine-serine, glutathione, and sphingolipid metabolism (p<0.03)—that are dysregulated in concurrent MASH and atherosclerosis. Sphingolipid severity also predicted disease severity. Hepatic levels of itaconate and lactate positively correlated with disease progression, while glycine, carnitine, 2-aminomuconic acid, and thiamine pyrophosphate showed negative associations (p<0.04). Lipidomics revealed disruptions in polyunsaturated fatty acids, steryl esters, and dihexosylceramides metabolism. Comparing mouse and human transcriptomes uncovered similar pathways involved in metabolism and inflammation/pro-atherogenesis. Our sex-specific multiomics approach established a mouse model of concurrent MASH and atherosclerosis, highlighting sex-dependent dietary effects and metabolic and transcriptional pathways as potential biomarkers and therapeutic targets.