Objective The existing work aims to assess the role of hesperidin against silver oxide nanoparticles-induced toxic changes in brain of adult albino rats. Methods 50 adult male albino rats were divided into four groups: group Ia (-ve control); group Ib (+ve control; saline group); group II (hesperidin (HN); each rat received 50 mg/kg/day orally); group III (AgNPs; each rat received 1 mg/kg/ day IP); and group IV (HN and AgNPs in the previous doses) all for 28 days. Then rats were anesthetized and killed, and specimens from the brain were taken for biochemical and histopathological studies. Results AgNPs exposure showed significantly increased tissue malondialdehyde (MDA), inducible nitric oxide synthase, caspase 8 and caspase 3 activities with significant depletions of superoxide dismutase activities. This was accompanied with alteration and damage in the histological structure of the brain. These changes were improved in the group receiving HN with AgNPs. Conclusion The results of this study showed that hesperidin had protective effects against AgNPs-induced toxicity in rat brain.