Recent studies have provided compelling evidence linking the composition of the gut microbiota, host diet, and host physiology. Prebiotics are substrates that are selectively utilized by host microorganisms, conferring health benefits. Prebiotics, such as prebiotic blends (PB), are commonly used worldwide in food processing. Here, microbiome-metabolomics was used to evaluate how PB affect gut microbes and metabolic functions in C57BL/6 J mice administered cefixime. We found favorable effects of PB on obesity outcomes. PB supplementation significantly increased the abundance of Bifidobacterium, Parabacteroides, Alloprevotella, Alistipes, and Dubosiella, and decreased that of Robinsoniella, Blautia, Lachnoclostridium, Coprobacillus, Hungatella, Erysipelatoclostridium, Helicobacter, Clostridium sensu stricto 1, Enterococcus, and Akkermansia compared to that in the cefixime administration (CEF) group. In particular, PB increased the abundance of Parabacteroides goldsteinii and suppressed that of Robinsoniella peoriensis and Akkermansia muciniphila. In addition, it regulated the levels of microbial metabolites such as unsaturated fatty acids and bile acids. Thus, PB can alleviate metabolic disorders induced by antibiotic intervention, indicating a potential dietary strategy for populations with antibiotic-associated diarrhea. KEY POINTS: • Prebiotic blends significantly increased the Parabacteroides goldsteinii colony. • Prebiotic blends selectivity reversed this increase of Akkermansia muciniphila by antibiotic intervention. • Prebiotic blends relieve cefixime-induced alteration of intestinal flora by regulating metabolites, such as fatty acids and bile acids.