Objective: To study the effects of resistant dextrin (RD) on liver fat deposition in high-fat diet-fed (HFD) mice, and to further explore whether it can regulate the AMPK signaling pathway. Methods: Thirty-six 4-week-old male C57BL/6 mice were randomly divided into three groups: normal control group (chow), high-fat diet group (HFD), and high-fat diet+ resistant dextrin group (HFD+ RD, 10 g·kg^-1·d^-1). After 12 weeks of intervention, the liver tissues and serum samples were collected. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), aspartate aminotransferase (AST), alanine transaminase (ALT) levels and liver TG were measured. Liver tissue HE and oil red O staining were performed to observe hepatocyte steatosis and liver fat deposition. Quantitative real-time PCR was performed to detect the relative expression of fatty acid synthesis related genes SREBP1, ACC, SCD1 in the liver tissue, and Western blot was performed to detect relative protein levels of pAMPK, SREBP1, Fasn, and ACC in the liver. Results: Compared with chow group, the body weight gain, fasting blood glucose (FBG), serum TC, LDL-C, HDL-C, and ALT levels were increased in HFD group (P<0.01), and serum AST level was also increased (P<0.05). Moreover, liver oil red O staining revealed that liver fat deposition was much more obvious in HFD group than that in chow group, and liver TG was also increased in HFD group (P<0.01). The mRNA levels of SREBP1 and ACC were increased in HFD group compared with that in chow group, and the protein level of pAMPK was reduced in HFD group (P<0.05). As compared with HFD group, the body weight gain, serum TG, TC, LDL-C, HDL-C and ALT levels were significantly reduced in RD group (P<0.01), and FBG level was also reduced (P<0.05). Moreover, RD treatment alleviated liver fat deposition and TG accumulation (P<0.01). The mRNA levels of SREBP1, ACC, and SCD1 were all reduced in RD group compared with HFD group. The protein level of pAMPK was increased, and the expression of Fasn was reduced with RD treatment (P<0.01). Conclusion Resistant dextrin improves liver fat deposition and activates the AMPK signaling pathway in HFD-fed mice.