Background: Radiodermatitis, a side effect of radiotherapy, presents as erythema, desquamation, skin necrosis or ulceration. Photobiomodulation therapy (PBMT) has been applied in diverse clinical fields with effects of reducing inflammation, acceleration of wound healing, and pain alleviation. Objectives: To evaluate the effect of PBMT for prevention of radiodermatitis and to evaluate skin changes histopathologically in an irradiated mouse model. Methods: Irradiated mice were randomly distributed into three groups: A (633 nm), B (830 nm), and C (without PBMT). On post-irradiation Day 7 and 21, we evaluated acute skin damage due to irradiation and compared irradiated skin to non-irradiated skin using H&E, Masson’s trichrome, anti-CD45 and PCNA immunohistochemistry, and a TUNEL assay. Results: Grade 3 radiodermatitis was evident only in Group C. Compared to Group C, Group A and B skin had significantly less epidermal hyperplasia, inflammatory cell infiltration, and thinner dermis on Day 7, and less inflammatory cell infiltration, fewer apoptotic cells, and thinner dermis on Day 21. However, there was no significant difference between Group A and B. Conclusion: This study indicates PBMT could prevent severe radiodermatitis by reducing epidermal and dermal damage, inflammation, and cellular apoptosis. There was no difference in PBMT efficacy between the 633 and 830 nm wavelengths.