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Nonalcoholic fatty liver disease (NAFLD) is defined by a set of hepatic conditions ranging from steatosis to steatohepatitis (NASH), characterized by inflammation and fibrosis, eventually predisposing to hepatocellular carcinoma (HCC). Together with fatty acids (FAs) originated from adipose lipolysis and hepatic lipogenesis, intestinal‐derived FAs are major contributors of steatosis. However, the role of mono‐unsaturated FAs (MUFAs) in NAFLD development is still debated. We previously established the intestinal capacity to produce MUFAs, but its consequences in hepatic functions are still unknown. Here, we aimed to determine the role of the intestinal MUFA‐synthetizing enzyme stearoyl‐CoA desaturase 1 (SCD1) in NAFLD. We used intestinal‐specific Scd1‐KO (iScd1−/−) mice and studied hepatic dysfunction in different models of steatosis, NASH, and HCC. Intestinal‐specific Scd1 deletion decreased hepatic MUFA proportion. Compared with controls, iScd1−/− mice displayed increased hepatic triglyceride accumulation and derangement in cholesterol homeostasis when fed a MUFA‐deprived diet. Then, on Western diet feeding, iScd1−/− mice triggered inflammation and fibrosis compared with their wild‐type littermates. Finally, intestinal‐Scd1 deletion predisposed mice to liver cancer. Conclusions: Collectively, these results highlight the major importance of intestinal MUFA metabolism in maintaining hepatic functions and show that gut‐derived MUFAs are protective from NASH and HCC. [ABSTRACT FROM AUTHOR]