The effectiveness of the synergistic effect of ultraviolet C irradiation with ozone (UVC+O3) for aflatoxin B1 (AFB1), ochratoxin A (OTA), and fumonisin B1 (FB1) detoxification in naturally contaminated poultry feeds with their impacts on the feed nutritional components were investigated. Feed samples were exposed to UVC+O3 for six durations (10, 20, 30, 60, 120, and 180 min) at three distances (15, 30, and 60 cm) with UVC doses ranging between 577.8 to 10400.4 mJ/cm2 at 15 cm, 397.8 to 7160.4 mJ/cm2 at 30 cm, and 50.4 to 907.2 mJ/cm2 at 60 cm at a constant O3 concentration of 10 ppm. Mycotoxin levels were determined by competitive Enzyme-Linked Immunosorbent Assay (ELISA) and results were confirmed by High-Performance Liquid Chromatography (HPLC). Feed component analysis with peroxide values (PVs) appreciation was executed according to standard analytical methods. A significant increase (P<0.05) in degradation percentages of AFB1, OTA, and FB1 was recorded with increasing exposure time and decreasing distances to reach values of 80.94, 84.07, and 83.6% at 15 cm, 78.49, 83.89, and 83.89% at 30 cm and 67.9, 74.76, and 72.89% at 60 cm, respectively after 180 min of treatment. OTA and FB1 showed degradation levels significantly higher (P<0.05) than those recorded for AFB1. Feed components were intermediately affected by UVC+O3 treatment. Feed fats were still having good quality depending on PVs estimation. In brief, the efficiency of the synergistic effect of UVC+O3 in AFB1, OTA, and FB1 detoxification from poultry feed with a moderate impact on feed quality.