Physalis alkekengiL. calyx (PC) extract can relieve insulin resistance and has glycemic and anti-inflammatory effects; however, the potential mechanisms related to gut microbiota and metabolites remain elusive. This study aimed to understand how PC regulates gut microbiota and metabolites to exert anti-obesogenic effects and relieve insulin resistance. In this study, a high-fat high-fructose (HFHF)-diet-induced obesity C57BL/6J male mice model with glycolipid metabolism dysfunction was established, which was supplemented with the aqueous extract of PC daily for 10 weeks. The results showed that the PC supplementation could effectively cure the abnormal lipid metabolism and maintain glucose metabolism homeostasis by regulating the expression of adipose metabolic genes and glucose metabolism genes in the liver, thereby effectively alleviating the inflammatory response. PC treatment also increased the contents of fecal short-chain fatty acids (SCFAs), especially butyric acid. PC extract could restore the HFHF-disrupted diversity of gut microbiota by significantly increasing the relative abundance ofLactobacillusand decreasing those ofRomboutsia,Candidatus_Saccharimonas, andClostridium_sensu_stricto_1. The negative effects of the HFHF diet were ameliorated by PC by regulating multiple metabolic pathways, such as lipid metabolism (linoleic acid metabolism, alpha-linolenic acid metabolism, and sphingolipid metabolism) and amino acid metabolism (histidine and tryptophan metabolism). Correlation analysis showed that among the obesity parameters, gut microbiota and metabolites are directly and closely related. To sum up, this study suggested that PC treatment exhibited therapeutic effects by regulating the gut microbiota, fecal metabolites, and gene expression in the liver to improve glucose metabolism, modulate adiposity, and reduce inflammation.