Background: Malnourishment is a common complication in patients with Crohn’s disease. Methods: An observational, prospective study was conducted to assess the nutritional status, disease activity, and stool frequency at baseline and after 12 weeks of treatment with a semi-elemental diet in patients with active Crohn’s disease. Results: A total of 144 patients with Crohn’s disease were included. The nutritional status improved after treatment, resulting in 76.1% of patients at low risk of malnourishment, 20.4% moderately malnourished, and 8.5% severely malnourished after 12 weeks of treatment. Nutritional status improvement was associated with the number of nutritional supplements. Mean albumin levels and body mass index (BMI) improved after 12 weeks of nutritional treatment (from 3.0 g/dL to 3.7 g/dL and from 20.2 kg/m2 to 21.1 kg/m2, respectively). A significant decrease in HBI was found after 12 weeks of nutritional treatment (from 10.2 to 3.7). The mean number of stools per day decreased with the 12 week semi-elemental diet (from 4.6 stools/day to 1.7 stools/day). Conclusion: In this observational study, the semi-elemental diet seemed effective in improving the nutritional status, disease activity, and stool frequency in patients with active Crohn’s disease.