Background Zinc oxide nanoparticles are nanoparticles of metal oxide with semiconductor properties and proved many noxious effects on the mammalian cell. Sildenafil, a phosphodiesterase inhibitor, and chrysin, one of the flavonoids, proved to have anti‐inflammatory and anti‐oxidative stress effects. Methods 48 rats were grouped into 8 groups equally. 1. (Control group) received normal diet and NaOH was added to water, 2. (Chrysin group): 250 mg/kg, orally for 10 days, 3. (sildenafil group): 40 mg/kg, orally for 14 days, 4. (ZnO‐NPs group): 200 mg/kg, intraperitoneal for 10 days, 5. (ZnO‐NPs + Chrysin as a prophylactic agent): given in the same previ‐ ous doses and durations consecutively, 6. (ZnO‐NPs + Chrysin as a curative agent): given in the same previous doses and durations with chrysin given after ZnO‐NPs administration for 10 days, 7. (ZnO‐NPs + sildenafil as a curative agent): given in the same previous doses and durations with sildenafil given after ZnO‐NPs administration for 10 days, and 8. (Combined treatment group Chrysin + Sildenafil) as combined treatment were given in the same previous doses and durations after ZnO‐NPs administration for 10 days. Blood and samples from tissues were withdrawn for histopathological, biochemical studies, and comet assay at the end of the experiment. Results Sildenafil and chrysin proved to protect from hepatotoxicity and hematotoxicity induced by zinc oxide nanoparticles as they lessened aspartate transaminase, alanine transferase, and alkaline phosphatase levels. They also reduced the oxidative stress enzyme levels. Gene expression of myeloid differentiation factor 88, nuclear factor kappa B1, tumor necrosis factor, and DNA damage decreased with treatment. Also, there was an improvement in the histopathological picture of the liver seen with treatment. Concurrent administration of sildenafil and chrysin revealed much better improvement than either drug used alone. Conclusion Chrysin and sildenafil have ameliorative effects against ZnO‐NPs‐induced hepatotoxicity and hemato‐ toxicity, their protective effect is either preventive with chrysin or curative with chrysin and sildenafil. Keywords ZnO‐NPs, Sildenafil, Chrysin, MyD88, Hepatotoxicity, Hematotoxicity, TNF‐α.