BACKGROUND: Postoperative ileus occurs in up to 30% of patients following major oncologic surgery for colorectal cancer, leading to significant morbidity, patient distress, as well as increased utilization of healthcare resources. Various modalities to reduce postoperative ileus rates have been explored. One such modality is the perioperative administration of probiotics which have hitherto achieved inconsistent success. Here, we design a trial to determine whether the perioperative administration with probiotics given together with nutritional supplementation can help to reduce postoperative ileus rates. METHODS: We propose a parallel three-arm randomized controlled trial. In Arm 1, no nutritional supplementation is provided to the patient. In Arm 2, Nestle Isocal is provided to the participant. Nestle Isocal provides nutritional supplementation but without any probiotic. In Arm 3, Nestle Boost Optimum is provided to the patient. Nestle Boost Optimum contains a similar nutritional profile to Isocal, but with the addition of Lactobacillus paracasei. The primary outcome is the time to first bowel movement in days from the day of surgery. Secondary outcomes are time to first flatus, infective complications, and adverse events related to the administration of nutritional supplementation. Statistical analysis will be conducted in an intention-to-treat approach. ANOVA with the Tukey test will be used to compare continuous variables, while the χ DISCUSSION: Nutritional supplementation with probiotics is a convenient, non-pill alternative for patients. Furthermore, the interventions are commonly found in the formulary of many hospitals worldwide. If successful, probiotics in nutritional supplementation could be a cost-effective and simple way to reduce postoperative ileus. TRIAL REGISTRATION: ClinicalTrials.gov NCT06456229. This trial was registered on 11 June 2024. Thai Clinical Trials Registry TCTR20240706003. This trial was registered on 6 July 2024.