Exposure to nanoparticles became inevitable in our daily life due to their huge industrial uses. Copper oxide nanoparticles (CuONPs) are one of the most frequently utilized metal nanoparticles in numerous applications. Crocin (CRO) is a major active constituent in saffron having anti-inflammatory and antioxidant potentials. Objectives We designed this study to explore the probable defensive role of CRO against CuONPs-induced rat hepatic damage. Materials and methods Therefore, 24 adult rats were randomly distributed into 4 equal groups as negative control, CRO, CuONPs, and co-treated CuONPs with CRO groups. All treatments were administered for 14 days. The hepatotoxic effect of CuONPs was evaluated by estimation of hepatic alanine aminotransferase and aspartate aminotransferase enzymes, hepatic oxidative malondialdehyde and antioxidant glutathione reduced, serum levels of inflammatory biomarkers (tumor necrosis factor-alpha, interleukin-1-beta, and nuclear factor kappa B), and expression of the apoptotic BAX in hepatic tissues; in addition, histopathological examination of the hepatic tissues was conducted. Results We found that concurrent CRO supplement to CuONPs-treated rats significantly averted functional and structural rat hepatic damage as documented by decreased hepatic enzymes activities, restored hepatic oxidant/antioxidant balance, decreased serum levels of inflammatory biomarkers, reversed BAX-mediated apoptotic cell death in hepatic tissues along with repair of CuONPs-induced massive hepatic structural and ultrastructural alterations. Conclusions It is concluded that combined CRO supplement to CuONPs-treated rats improved hepatic function and structure by, at least in part, antioxidant, anti-inflammatory, and antiapoptotic mechanisms.