Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.