Background: Inflammatory bowel disease is one of the most serious health problems. Vortioxetine (VRT) is SSRIs and SNRIs as it has multimodal profile. Dapagliflozin (Dapa) , is SGLT2 inhibitor which might suppress the expression of inflammatory cytokine. Aim of the study: This work was designed to assess the potential prophylactic effect of VRT and Dapa alone and in combination in acetic acid induced UC in rats . Materials and Methods: This study was conducted on 36 adult rats, divided into 6 groups; (I) normal rats, (II) Non treated UC group, (III) sulfa treated UC group received sulfa (100 mg /kg/ day, orally), (IV) VRT treated UC group received VRT (10 mg/kg/day, orally), (V) Dapa treated UC group received Dapa (5mg/kg/day, orally) and (VI) VRT and dapa treated group received combination of VRT (10 mg/kg/day, oral) and dapa (5mg/kg/day, orally).Results: Treated groups showed significant decrease in colon weight, CMI , colon weight / length ratio, increase in colon length, improved in body weight , decrease in DAI, serum iNOS , CRP, colonic TNF-α , increase of colonic IL10, GSH decrease in colonic MDA, macroscopic examination and down regulation of Caspase-3 and TGFB-1 immuno expression compared with UC non treated rats. Conclusion: Current findings confirmed ameliorative impact of sulfa, VRT and dapa on UC. rats received combined therapy showed the best results as standard group (sulfa treated group ) but rats received mono therapy either VRT or dapa had the lowest prophylactic effect.