The recent study targeted to estimate the plain appliance of liver damage induced by either alone or combined treatments of zinc oxide nanoparticles (ZnO NPs) and mureer or Senecio glaucus L. plant (SP) via studying biochemical, histological, and genetic tests for 30 days, and to evaluate the prophylactic action of gallic acid (GA) in rats. Forty rats were orally treated and equally estranged into 8 groups with five rats in each group: Control, GA (100 mg/kg), ZnO NPs (150 mg/kg), SP (400 mg/kg), GA+ZnO NPs (100,150 mg/kg), GA+SP (100,400 mg/kg), ZnO NPs+SP (150,400 mg/kg), and GA+ZnO NPs+SP (100,150,400 mg/kg). This study tested DNA content via comet assay, mRNA expression of an anti-apoptotic gene (Bcl-2) and a pro-apoptotic gene (Bax) via real-time qPCR, (P < 0.001), and caspase-3 expression via immunohistochemical study. Outcomes revealed that alone and combined treated groups of ZnO NPs and SP significantly altered enzyme activity and incited oxidative damage. They made DNA breakup, raised Bax and Bax/Bcl-2 ratio levels, dwindled Bcl-2 level, overexpressed caspase-3, and then initiated histopathological variants. The deadly effect of combined treatment was more than the effect of alone treatment. In contrast, it displayed that GA moderated this injury. Lastly, it clinched that ZnO NPs and SP act as pro-apoptotic agents; yet, GA acts as an anti-apoptotic agent.