Ulcerative colitis (UC) is established by a chronic, diffuse inflammation of colonic mucosa with poorly defined etiology, and without sufficient treatment or cure available for remission. In this context, there is a growing recognition and consensus that synbiotic supplement may be promising and impactful strategies towards ameliorating UC and related inflammatory disorders, garnering significant attention from researchers as an alternative therapy. Herein, we innovatively prepared a novel synbiotic combination including Lactobacillus acidophilus, Bifidobacterium infants and prebiotics konjac glucomannan oligosaccharides (KGMO) to explore the potential therapeutic effects in dextran sodium sulfate (DSS) induced UC mouse model. The results demonstrated that the synbiotic effectively improved colitis symptoms in mice by mitigating weight loss, disease activity index (DAI), colonic pathological damage, and colonic oxidative stress. it also observed that the synbiotic preserve intestinal barrier function integrity, reduces metabolic endotoxemia as well as inhibits the TLR4/NF-κB, NLRP3/Caspase-1, and Nrf2/Keap1 signaling pathway. Furthermore, the synbiotic modulated microbial homeostasis directly by enhancing beneficial microbes and reducing potentially harmful bacteria. In addition, microbiome phenotype prediction and bacterial functional potential prediction analysis demonstrated that the synbiotic supplementation regulated gut microbiota function involving inflammatory injury, metabolism, immune response, and pathopoiesia. Especially, the synbiotic not only restored the balance of Th1/Th2 cells as well as Th17/Treg cells along with specific inflammatory factors expression, but also maintained bile acid homeostasis by regulating FXR/FGF15 signaling pathway. Especially important is that the synbiotic was as effective as mesalazine against UC. According to above data, it is seen that this novel synbiotic could be a good candidate drug for ameliorating UC through its anti-inflammatory, antioxidant stress, antipyroptosis properties, regulation of bile acid metabolism, and remission of endothelial dysfunction and gut dysbiosis.