Abstract Background Serum protein biomarkers are used to diagnose, monitor treatment response, and to differentiate various forms of chronic enteropathies (CE) in humans. The utility of liquid biopsy proteomic approaches has not been examined in cats. Hypothesis/Objectives To explore the serum proteome in cats to identify markers differentiating healthy cats from cats with CE. Animals Ten cats with CE with signs of gastrointestinal disease of at least 3 weeks duration, and biopsy-confirmed diagnoses, with or without treatment and 19 healthy cats were included. Methods Cross-sectional, multicenter, exploratory study with cases recruited from 3 veterinary hospitals between May 2019 and November 2020. Serum samples were analyzed and evaluated using mass spectrometry-based proteomic techniques. Results Twenty-six proteins were significantly (P < .02, ≥5-fold change in abundance) differentially expressed between cats with CE and controls. Thrombospondin-1 (THBS1) was identified with >50-fold increase in abundance in cats with CE (P < 0.001) compared to healthy cats. Conclusions and Clinical Importance Damage to the gut lining released marker proteins of chronic inflammation that were detectable in serum samples of cats. This early-stage exploratory study strongly supports THBS1 as a candidate biomarker for chronic inflammatory enteropathy in cats.