Ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), is a chronic tissue-destructive disorder of the colon. Current laboratory diagnostic assays depend on evaluation of calprotectin that boost with the advancement of the diseases. The present study aimed to evaluate activin-A as a potential alternative marker for early detection of ulcerative colitis (UC). Experimental murine models of short-term versus long-term dextran sodium sulphate (DSS)-induced UC were developed and assessed histopathologically for evaluation purposes. Immunoassays were adopted for evaluation of both activin-A and calprotectin levels in collected serum and fecal specimens using commercial ELISA kit. Colon tissue specimens were homogenized and used for evaluation of activin-A and calprotectin gene expression using quantitative real-time PCR. The results revealed significant increases in serum and fecal activin-A in both short-term and long-term colitis models while there was a significant increase of fecal calprotectin only in long-term UC. Evaluation of gene expression revealed significant upregulation of activin-A in short-term but not in long-term UC model, whereas calprotectin expression showed significant upregulation in long-term but not in short-term of UC model. Interestingly, strong positive correlation was evident between serum, fecal and gene expression of activin-A in both short-term and long-term UC models. On the other hand, calprotectin showed negative correlation between serum and fecal levels in long-term model and positive correlation between serum and gene expression levels in short-term UC. In conclusion, while fecal calprotectin is a good indicator for late stage UC, serum activin-A is a potential biomarker that promote early prognosis of UC.