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Natural pentacyclic triterpenoid oleanolic acid (OA) is used as an over‐the‐counter drug for acute and chronic hepatitis. However, clinical use of OA‐containing herbal medicines has been reported to cause cholestasis, and the specific mechanism is unknown. The purpose of this study was to explore how OA causes cholestatic liver injury via the AMP‐activated protein kinase (AMPK)‐farnesoid X receptor (FXR) pathway. In animal experiments, it was found that OA treatment activated AMPK and decreased FXR and bile acid efflux transport proteins expression. When intervened with the specific inhibitor Compound C (CC), it was observed that AMPK activation was inhibited, the reduction of FXR and bile acid efflux transport protein expression was effectively alleviated, serum biochemical indicators were significantly reduced, and liver pathological damage brought about by OA was effectively ameliorated. In addition, OA was found to downregulate the expression of FXR and bile acid efflux transport proteins by activating the ERK1/2‐LKB1‐AMPK pathway in cellular experiments. The ERK1/2 inhibitor U0126 was used to pretreat primary hepatocytes, and this drastically reduced the phosphorylation levels of LKB1 and AMPK. The inhibition effects of OA on FXR and bile acid efflux transport proteins were also effectively alleviated after pretreatment with CC. In addition, OA‐induced downregulation of FXR gene and protein expression levels was significantly prevented after silencing AMPKα1 expression in AML12 cells. Our study demonstrated that OA inhibited FXR and bile acid efflux transporters through the activation of AMPK, thus leading to cholestatic liver injury. Oleanolic acid (OA) is used as an over‐the‐counter drug for the treatment of liver diseases, but clinical use of OA‐containing herbal medicines can lead to cholestasis. In this study, OA was found to induce liver injury by activating AMPK phosphorylation through the ERK1/2‐LKB1 pathway and inhibiting FXR and its downstream targets. Silencing of AMPKα1 in cells attenuated OA‐induced FXR inhibition. Pharmacological inhibition of AMPK in cells and animals has a protective effect against OA‐induced liver injury. [ABSTRACT FROM AUTHOR]