As shown in Graphical Abstract, our study firstly demonstrated that geniposide was capable to protect mice and cells from NAFLD‐induced oxidative stress and inflammation which mostly depended on up‐regulating the Nrf2 and adjusting the protein expression of AMPK/PI3K/mTOR signalling pathways. This evidence concerns the gene PRKAB1 and metabolic dysfunction-associated steatotic liver disease.