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This study was conducted to compare the synbiotic activity between <i>Corni fructus</i> (<i>C. fructus</i>) and <i>Limosilactobacillus reuteri</i> (<i>L. reuteri</i>) on dextran sulfate sodium (DSS)-induced colitis and cognitive dysfunction in C57BL/6 mice. <i>C. fructus</i> (as prebiotics, PRE), <i>L. reuteri</i> (as probiotics, PRO), and synbiotics (as a mixture of <i>L. reuteri</i> and <i>C. fructus</i>, SYN) were fed to mice for 3 weeks. Consumption of PRE, PRO, and SYN ameliorated colitis symptoms in body weight, large intestinal length, and serum albumin level. Moreover, SYN showed a synergistic effect on intestinal permeability and intestinal anti-inflammation response. Also, SYN significantly improved cognitive function as a result of measuring the Y-maze and passive avoidance tests in DSS-induced behavioral disorder mice. Especially, SYN also restored memory function by increasing the cholinergic system and reducing tau and amyloid β pathology. In addition, PRE, PRO, and SYN ameliorated dysbiosis by regulating the gut microbiota and the concentration of short-chain fatty acids (SCFAs) in feces. The bioactive compounds of <i>C. fructus</i> were identified with quinic acid, morroniside, loganin, and cornuside, using ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS²). In conclusion, synbiotic supplementation alleviated DSS-induced colitis and cognitive dysfunction by modulating gut microbiota, proinflammatory cytokines, and SCFAs production.