Skin toxicity is a ubiquitous side effect in radiotherapy and can be difficult to predict. Moist desquamation in cancer patients can decrease quality of life and occasionally demand unplanned treatment breaks thus worsening outcome. In breast cancer patients, moist desquamation occurs approximately one-third of the time, and while avenues such as intensity-modulated radiation therapy exist to decrease skin side effects, they may be prohibitively expensive to distribute widely. To selectively target patients who are at risk for high skin toxicity, toxicity prediction beyond heuristics is required. This study presents 3D thermal tomography, a translation technology that employs active thermal imaging to map the thermal effusivity of skin. Irradiated mice were imaged throughout reaction development to establish a correlation between effusivity changes and eventual toxicity severity. Female hairless mice (n = 11) were anesthetized and irradiated to 40 Gy in one fraction using a 1 cm Leipzig brachytherapy applicator with an Ir-192 source. After irradiation, thermal imaging was conducted daily with a flash lamp and infrared camera. Effusivity was calculated using custom software and tracked within irradiated and contralateral control regions. Mice were retrospectively grouped into high-grade (moist desquamation present, n = 6) and low-grade (n = 5). All mice showed an increase in the relative average effusivity difference among the treated and control regions between irradiation and peak reaction between 12 and 15 days after irradiation. The high-grade group showed an earlier increase in relative average effusivity difference (mean 1.7 days after irradiation versus 4.4 days after irradiation) than the low-grade group, and had a significantly greater relative average effusivity difference between 2–5 days after irradiation. We concluded that 3D thermal tomography is quick, non-invasive, non-ionizing and exhibited a correlative difference between mice that eventually developed moist desquamation and those that only presented dry desquamation. With further development, it may prove to be a useful tool in the clinic for differentiating patients who require preventative measures to reduce skin toxicity.