Inflammatory bowel disease (IBD) is a chronic, multifactorial disorder of the gastrointestinal tract, often associated with dysbiosis in gut microbiota. While the exact cause of IBD remains unclear, alterations in gut microbiome composition and function are recognised as key contributors to IBD pathogenesis. Natural compounds with anti-inflammatory properties are increasingly explored as potential therapeutic options for IBD. This study evaluated the therapeutic effects of two newly isolated galloyl glucosides-galloyl-lawsoniaside A (comp-4) and uromyrtoside (comp-6)-alongside dexamethasone (DEX) on microbiome regulation in a 2, 4, 6-Trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model. We employed PacBio HiFi full-length 16S rRNA gene sequencing on mouse colon tissue to assess changes in the intestinal microbiome and its associated functional pathways. TNBS-induced colitis significantly altered microbial composition, increasing the abundance of Acutalibacter muris, Monoglobus pectinilyticus, Streptococcus pneumoniae, Parabacteroides merdae, and Haemophilus influenzae, while decreasing Staphylococcus ureilyticus and Mailhella massiliensis. Treatment with comps 4 and 6 effectively restored the imbalanced microbiota. Functional pathway analysis revealed that colitis reduced microbial pathways, including peptidoglycan biosynthesis and the Bifidobacterium shunt. These disruptions were restored following treatment with our plant-derived compounds. Functional improvements were likely associated with reduced IL-6 production and restoring intestinal barrier integrity. Notably, comp-4 exhibited the most pronounced therapeutic efficacy across both microbial and host-associated parameters. In silico docking further supported the anti-inflammatory and immunomodulatory potential of these compounds. Together, our findings highlight the interplay between microbial function and host immunity in IBD and identify plant-derived galloyl glucosides as promising candidates for microbiome-targeted IBD therapeutics.