This study aimed to elucidate the antiobesity mechanisms of sweet potato extract (SPE) through biochemical, gut microbiome, liver transcriptome, and metabolome analyses. Administration of SPE to high-fat-diet-fed mice significantly reduced body weight gain, serum low-density lipoprotein cholesterol, hepatic lipid accumulation, and adipocyte hypertrophy, which were closely linked to gut microbiome composition. SPE notably increased the abundance of Eubacterium_coprostanoligenes_group_unclassified and decreased that of Kineothrix, both of which were strongly associated with short-chain fatty acid (SCFA) production. LC-QTOF-MS analysis identified resin glycoside compounds from SPE with reduced levels in mouse feces, suggesting their utilization in vivo. SPE also promoted dietary fat excretion. Liver transcriptomic and metabolomic profiling revealed that SPE may exert antiobesity effects by modulating the bile-sphingolipid metabolism, which was closely correlated with the reshaped gut microbiomes and SCFAs. These findings provide new insights into the antiobesity effects and mechanisms of SPE.