Abstract Background Radiation therapy is the most prescribed treatment for many oncologic indications. One of its common side effects is mucositis with hallmark apoptosis in the intestinal crypt and diarrhea. Objective We investigated the potential beneficial effects of etanercept and cyclosporin treatment during radiation exposure. The effects of these drugs on intestinal apoptosis, long-term weight loss, diarrhea severity, and survival were examined. Methods For acute observation studies, animals pretreated with phosphate buffer saline (PBS) vehicle, either etanercept, or cyclosporin were challenged with either 1 Gy or 13 Gy irradiation and sacrificed 6 hours later. The animals' small intestines were then harvested for histologic analysis. For chronic survival studies, 14.5 Gy irradiation was applied. Etanercept or cyclosporin treatments were given 15 minutes before the irradiation, followed by daily administration. Results At 6 hours postirradiation the maximum apoptotic index observed in the small intestine was ∼25% for both 1 Gy and 13 Gy irradiation. Etanercept and cyclosporin pretreatment had no effect on the irradiation-induced apoptosis. During chronic observation, the rate of weight loss was similar in all test groups. At 7 days postirradiation, the weight loss in phosphate buffered saline-treated control, etanercept, and cyclosporin groups reached a maximum at 19%, 24%, and 31.8%, respectively. The weight lost in the cyclosporin group was significantly higher than in the control group. Neither treatment reduced the severity of diarrhea, but cyclosporin increased the survival rate. Sixty percent of cyclosporin-treated animals survived compared with 27% in the PBS-treated control group and 47% in the etanercept-treated group. Serum tumor necrosis factor-α levels, a biomarker for both etanercept's mechanism of action and treatment efficacy, was inhibited by etanercept throughout the study, but cyclosporin only showed an inhibitory effect at 48 hours postirradiation. Conclusions Our study demonstrates that cyclosporin increases the survival rate of irradiated animals without affecting parameters such as intestinal histology, weight loss, and diarrhea severity.