Background: Chemoradiotherapy-induced gastrointestinal toxicity may lead to a significant impairment of the oncological patient’s quality of life, as well as to reduced adherence to the treatment, which may have a negative impact on survival and mortality rates. Objective: The aim of this review was to investigate whether oral probiotic administration prevents chemotherapy (± radiotherapy)-induced gastrointestinal toxicity, particularly diarrhea. Methods: We searched the MEDLINE, Web of Science, and SCOPUS databases for randomized controlled trials in English published between 1990 and 2020. We conducted statistical data analyses expressing the treatment effect size as a risk ratio (RR) together with a 95% confidence interval (CI). Implications are based on trials rated as having a low risk of bias (RoB). Results: We included 8 trials (n=697 participants), from which 3 studies rated as low RoB contained primary endpoint data; the risk of developing grade 3/4 diarrhea in patients receiving probiotics was reduced by 78% compared to the control group (RR=0.22 [95% CI 0.05-1.08]; P=.06; n=114 participants). Probiotics showed preventive effects in patients treated with chemotherapy alone (RR=0.34 [0.12-0.94]; P=.04, n=121 participants) and in patients with colorectal cancer (RR=0.56 [0.34-0.92]; P=.02; n=208 participants). The reduction in the incidence of overall diarrhea was not significant. Conclusions: Probiotics failed to prove a preventive effect of statistical significance against the development of severe and overall diarrhea in cancer patients treated with chemotherapy (± radiotherapy). However, we cannot rule out that the effects of probiotics are clinically relevant, especially in certain subgroups of patients. This needs to be clarified in further well-performed studies.