Inflammatory bowel disease (IBD) refers to chronic immune-mediated conditions. Damage to the intestinal barrier is associated with changes in bacterial product levels and the systemic inflammation persistence. The mucosal barrier molecular components, such as I-FABP, mucin 2, TFF2, and TFF3, are involved in maintaining the epithelium integrity and the inflammatory response modulation. However, the diagnostic value of those in IBD is still poorly understood. The single center cross-sectional comparative study aimed to perform a comprehensive comparative assessment of the mucosal barrier serum components in healthy donors and patients with IBD. A total of 20 patients with IBD and 20 healthy donors were enrolled. Serum concentrations of I-FABP, mucin 2, TFF2, and TFF3 were determined by the enzymelinked immunosorbent assay. Statistical analysis was conducted using the Mann–Whitney U-test, the differences were considered significant at p ≤ 0.05. Significant differences were reported for TFF2 and TFF3. In patients with IBD, TFF2 levels were 5 times higher, than in healthy donors, and TFF3 levels were 4.2 times higher. Thus, serum levels of TFF2 and TFF3 are elevated in IBD, which reflects activation of the repair mechanisms and can be considered as an inflammatory activity marker.