Ulcerative colitis, particularly the chronic persistent form is characterized by the presence of active inflammation and extensive areas of ulceration in the colonic mucosa. The existing treatment protocol aims at only reducing intestinal inflammation, rather than targeting mucosal ulceration. In this study, type I collagen and its daughter peptides called collagen hydrolysate, highly popular reconstructive materials for tissue engineering applications, are hypothesized as healing matrices to target the recuperation of internal mucosal ulceration. The clinical assessments on day 10 of dextran sodium sulfate induced colitis in mice model revealed that both the collagen (1.56 ± 0.29) and collagen hydrolysate treatments (1.33 ± 0.33) showed a significant reduction in the rectal bleeding compared to the reference mesalamine treatment (2.50 ± 0.33) and untreated negative control (2.40 ± 0.40). VEGF, a potent angiogenic growth factor, over expressed during UC was down-regulated by collagen hydrolysate (1.06 ± 0.25) and collagen (1.76 ± 0.45) to a greater extent than by mesalamine (2.59 ± 0.51) and untreated control (4.17 ± 0.15). The down-regulation of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 also follows the same pattern. Histological observations were in accordance with the clinical indicators. Both collagen and collagen hydrolysate treatments showed significant reduction in mucosal damage score and facilitated faster regeneration of damaged mucosa.