(1) Background: Poor nutritional status and diarrhea are common complications in cancer patients. (2) Methods: This multicenter, observational, prospective study evaluated the effectiveness of an oligomeric enteral nutrition (OEN) protocol in the improvement of nutritional status and reduction of diarrhea symptoms. Nutritional status was assessed with the Subjective Global Assessment (SGA), Body Mass Index (BMI) and albumin levels. Diarrhea was evaluated by the frequency and consistency of stools (Bristol Stool form scale). (3) Results: After 8 weeks of OEN protocol, the nutritional status improved in 48.3% of patients, with an increased proportion of patients at risk of malnourishment (+27.3%) at the expense of a decrease of moderately (−19.9%) and severely (−7.3%) malnourished patients (p < 0.001). Serum albumin and BMI significantly increased after 8 weeks of OEN treatment (p < 0.005). OEN showed a 71.1% effectiveness in the improvement of stool consistency. The mean number of stools per day significantly decreased from baseline (4.17 stools/day) to week 8 (1.42 stools/day; p = 0.0041). The nutritional status significantly improved even in those patients with persistent diarrhea. (4) Conclusion: The proposed OEN protocol seemed to be effective in improving the nutritional status, frequency and consistency of stools in patients with oncology treatment-related diarrhea even in persistent cases.