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Background Ulcerative colitis (UC) frequently co-occurs with anxiety disorders, yet effective dual-target therapies remain scarce. Hyperoside (HYP), a natural flavonoid, possesses anti-inflammatory and neuroprotective properties, but its effects on UC and comorbid anxiety are poorly understood.Methods DSS-induced colitis mice were treated with HYP. Disease activity was assessed via body weight, colon length, and histopathology. Anxiety-like behaviors were evaluated using the open field and elevated plus maze tests. Neuroinflammation was examined through BDNF expression and microglial activation. Gut microbiota and metabolomics were analyzed via metagenomic sequencing and the Q300 Kit. Network pharmacology, molecular docking, and Western blotting were used to predict and validate signaling pathways. Microbiota dependency was determined through antibiotic depletion.Results HYP significantly ameliorated DSS-induced colitis, evidenced by attenuated weight loss, restored colon length, and reduced inflammatory cytokines (TNF-α, IL-6, IL-1β), while enhancing intestinal barrier integrity (Mucin-2, ZO-1). HYP also alleviated anxiety-like behaviors and neuroinflammation by increasing BDNF and suppressing microglial activation. It restored gut microbial homeostasis by enriching beneficial Enterobacter ludwigii and reducing pathogenic bacteria, and promoted arginine biosynthesis. Network pharmacology identified MAPK, PI3K-Akt, and NF-κB as key pathways, with HYP showing strong binding affinity to MAPK3, AKT1, and NFκB1. Crucially, HYP’s therapeutic effects were abolished in microbiota-depleted mice.Conclusions HYP alleviates DSS-induced colitis and comorbid anxiety in a microbiota-dependent manner by restoring microbial homeostasis, enhancing arginine metabolism, and modulating MAPK/PI3K-Akt/NF-κB pathways, positioning it as a promising therapeutic candidate for UC and its neuropsychiatric comorbidities.