Obesity and its comorbidities are a severe public health problem worldwide. The use of bioactive compounds found in some foods has been demonstrated to ameliorate the metabolic abnormalities associated with obesity. The purpose of this study was to assess whether the bioactive compounds present in aguamiel concentrate (AC) from Agave salmiana could attenuate glucose intolerance and hepatic steatosis in mice fed a high fat (HF) diet. HPLC-ELSD analysis showed that AC contained several saponins. The consumption of an AC extract rich in saponins reduced weight gain and fat mass and lowered serum glucose, insulin and LDL-cholesterol levels in mice fed a HF diet. Additionally, mice fed the saponin extract exhibited a reduced HOMA index and hepatic lipid levels and increased expression of genes involved in fatty acid oxidation. Saponins increased white adipose tissue browning, AMPK phosphorylation, fatty acid oxidation, and mitochondrial activity in skeletal muscle and energy expenditure in mice fed the HF diet. These metabolic changes were accompanied by an increase in the abundance of Akkermansia muciniphila in the gut microbiota. Therefore, Agave salmiana saponins can be an alternative to attenuate the metabolic changes that accompany obesity.