Purpose <p>Acute gastrointestinal (GI) toxicities are common side effects of pelvic radiotherapy in gynecologic cancers. Although bacterial probiotics show promise, there is limited evidence for yeast-based probiotics such as <i>Saccharomyces boulardii</i>. This study aimed to evaluate the efficacy of <i>S. boulardii</i> in preventing acute radiation-induced GI toxicities in patients undergoing pelvic radiotherapy for cervical and endometrial cancers.</p> Methods <p>A prospective, randomized, double-blind, controlled trial was conducted with 60 patients receiving definitive or postoperative pelvic radiotherapy. Patients were randomized to receive either <i>S. boulardii</i> (250 mg/day) or a placebo, starting one week before radiotherapy and continuing throughout treatment. Acute GI toxicities were assessed weekly using the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Stool consistency and inflammatory markers were also monitored. The primary outcome was the reduction in the severity of diarrhea and other GI symptoms.</p> Results <p><i>S. boulardii</i> significantly reduced the incidence of type 6 and 7 stool consistency at week 3 (<i>p</i> = 0.01). However, despite this transient improvement, the treatment group experienced a significantly higher incidence of diarrhea at week 4 compared to the control group (<i>p</i> = 0.03). Overall, no significant differences were found between the groups in terms of cumulative GI toxicities or anti-diarrheal medication use, with diarrhea remaining the most common acute GI toxicity in both groups.</p> Conclusion <p>No consistent effect of <i>S. boulardii</i> was observed across the measured outcomes, and its overall efficacy in preventing acute radiation-induced enteritis remains inconclusive. Further studies with larger sample sizes are warranted.</p> <p><b>Trial registration:</b> The study was registered with the Thai Clinical Trials Registry (TCTR20210204013) on 04 February 2021.</p>