Humans are exposed to different contaminants including mycotoxins. Deoxynivalenol (DON), a potent ribosome inhibitor, is a highly prevalent mycotoxin in the food chain worldwide. Although DON is not genotoxic, we previously showed that it exacerbates the genotoxicity of colibactin, a DNA-crosslinking toxin produced by bacteria in the gut. In the present study, we investigated whether this phenotype can be extended to other genotoxic compounds with different modes of action. Our data showed that, at a dose that can be found in food, DON exacerbated the DNA damage caused by etoposide, cisplatin and phleomycin. In contrast, de-epoxy-deoxynivalenol (DOM-1), a modified form of DON that does not induce ribotoxic stress, did not exacerbate DNA damage. The effect of DON was mimicked with other ribosome inhibitors such as anisomycin and cycloheximide, suggesting that ribotoxicity plays a key role in exacerbating DNA damage. In conclusion, a new effect of DON was identified, this toxin aggravates the DNA damage induced by a broad spectrum of genotoxic agents with different modes of action. These results are of utmost importance as our food can be co-contaminated with DON and DNA-damaging agents.