Background: Chronic intestinal inflammation results in tissue damage partly caused by an increase in matrix metalloproteinases (MMP) activity causing degradation of extracellular matrix (ECM) proteins. We studied intestinal tissue remodeling by quantifying ECM protein fragments in serum in dextran sulfate sodium (DSS)-induced colitis, to investigate ECM protein fragments as serological biomarkers of intestinal tissue remodeling and disease activity. Methods: Male Sprague–Dawley rats received 5% DSS in drinking water for 5 days followed by 11 days with regular water. Disease activity index (DAI) was scored daily. Serum was collected on day 0, 6, 7, and 16. ELISAs were used to quantify MMP-derived remodeling fragments of basement membrane type IV collagen (C4M and PRO-C4) and interstitial matrix type III collagen (C3M and rPRO-C3). Results: In DSS rats, serum levels relative to baseline of C4M, PRO-C4, and C3M were elevated (P < 0.01; P < 0.001; P < 0.001) at day 7, which declined at day 16. Levels of rPRO-C3 were lower in DSS rats at day 7 and increased to normal levels at day 16. The ratio between C3M and rPRO-C3 showed an overall degradation (P < 0.0001) of collagen type III in DSS rats at day 7, which correlated to the DAI (r 2 = 0.5588, P < 0.0001). Conclusion: Our data suggest that remodeling of the basement membrane (C4M and PRO-C4) and the interstitial matrix (C3M and rPRO-C3) increased during DSS-induced colitis and declined with reversal of the disease. Thus, serological biochemical biomarkers of the ECM reflect tissue remodeling and could be studied as markers of disease activity in IBD.