Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Developing safe and effective strategies to prevent NAFLD progression has become a hot topic. Geraniin is a natural polyphenolic compound abundant in fruit peels and possesses antioxidant and anti-inflammatory activities. This study used a high-fat diet (HFD)-induced NAFLD mouse model to investigate whether geraniin could prevent the development of NAFLD. The results showed that geraniin improved lipid profiles and insulin sensitivity in NAFLD mice, reduced inflammatory factors and oxidative damage, and modulated liver histopathology. mRNA sequencing and Western blot analysis indicated that the beneficial effects of geraniin may be related to the activation of the AMPK/PPAR and NRF2/HO-1 signaling pathways, and the suppression of the NF-κB signaling pathway in the liver. Further liver microRNA sequencing and in vitro experiments revealed that geraniin downregulates miR-34a-5p, thereby upregulating PGC1α expression, leading to the amelioration of lipid abnormalities and oxidative damage in the liver. Overall, geraniin improved HFD-induced NAFLD in mice through multiple beneficial effects, including antioxidant, anti-inflammatory, and improvement of lipid metabolism and insulin sensitivity, and geraniin ameliorated lipid abnormalities and oxidative damage in NAFLD in part by modulating the miR-34a-5p-PGC1α axis in the liver. In conclusion, this study shows that geraniin has potential as a natural therapeutic compound for NAFLD in humans.