Background: Homocysteine (HCY) was evaluated in healthy and chronic enteropathic dogs, however no studies on dogs with immunosuppressant-responsive enteropathy are available. Objectives: The aim was to evaluate serum HCY concentrations and its prognostic role in dogs with immunosuppressant-responsive enteropathy compared to healthy dogs. Methods: Serum HCY concentration was statistically compared between 24 healthy dogs and 29 dogs with immunosuppressant-responsive enteropathy. Correlation analyses between serum total protein, albumin (ALB), C-reactive protein (CRP), folate and cobalamin, and serum HCY concentration were performed in immunosuppressant-responsive enteropathic dogs. Results: The associations between serum HCY concentration and clinical, histological, endoscopic scores and follow-up were evaluated. Mean serum HCY concentration was higher in immunosuppressant-responsive enteropathic dogs compared to control dogs (30.22 ± 8.67 μmol/L vs. 5.26 ± 2.78 μmol/L; p < 0.0001). No association between serum HCY concentration and total protein, ALB, CRP, folate concentration as well as, clinical score, histological and endoscopic scores was found. A negative correlation between serum HCY concentration and cobalamin was noted (p = 0.0025, r = −0.54). No significant difference in HCY was found between responsive and non-responsive dogs or between survivors and non-survivors. Conclusions Although, serum HCY concentration was higher in immunosuppressant-responsive enteropathy, its prognostic value remains unclear. However, further prospective, large-scale studies are warranted to better investigate the possible prognostic role of HCY in immunosuppressant-responsive enteropathic dogs.