Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon part of the large intestine. Since there is no cure for this disease, conventional therapies only provide symptomatic relief. Recently, phytomolecules have shown promising treatment results in various diseases. However, short half-life, hydrophobicity, and poor bioavailability limit their therapeutic potential. To overcome all these challenges, we have earlier conjugated a phytomolecule (gallic acid) (GA) with the FDA-approved generally recognized as safe (GRAS) material that is glycerol monostearate (GMS). This GA-GMS conjugate self-assembles as a hydrogel via the heating-cooling method and acts as a pro-drug of GA. The in vivo imaging results suggest that the GA-GMS hydrogel more efficiently adheres to the inflamed colon than a therapeutic enema. Additionally, it is known that the gut microbiota exaggerates UC by creating a hypoxic environment in the colon. This hypoxia is linked with NLRP3 inflammasome activation that triggers the release of IL-1beta and IL-18 that downregulates MUC2 protein expression in the colon, responsible for mucin secretion in the colon. Therefore, chrysin (CR) (HIF-1alpha inhibitor) is encapsulated into the GA-GMS hydrogel to target hypoxia. The CR@GA-GMS hydrogel follows the enzyme-responsive release of the CR and restores DSS-induced damage to colonic tissue. Furthermore, the CR@GA-GMS hydrogel downregulates HIF-1alpha mediated NLRP3 inflammasome signalling while upregulating MUC2 production.