Objective: In the present study, we explored the therapeutic potential of citicoline in preventing malathion induced neurotoxicity and genotoxicity. Citicoline has been shown to act as a neuroprotective in experimental animal models of ischemia and other types of brain injuries. Methods: Acute malathion intoxication was induced by intraperitoneal injection of malathion (150 mg/Kg, once per day) for two successive days. Citicoline was co-administered in three doses (100, 200, 300 mg/kg, p.o.). Serum Butyrylcholine esterase (BChE) and Paraoxonase-1 (PON-1) were assessed as exposure biomarkers. Oxidative stress biomarkers were assessed in the different brain regions (cortex, striatum, and subcortex) in addition to TNF-α. Genotoxicity was tested by chromosomal aberrations, mitotic index, DNA fragmentation, and micronucleus tests. Results: Malathion administration resulted in marked suppression of serum BChE and PON-1 activities. Also, the exposure to the pesticide led to elevated malondialdehyde (MDA), nitric oxide (NO), and decreased reduced glutathione (GSH) levels in investigated brain regions in addition to elevated striatal tumor necrosis factor-α (TNF-α) level. Malathion also caused profound structural chromosomal aberrations, increased liver DNA fragmentation, and mitotic index. These effects were alleviated with the administration of citicoline dose-dependently. Conclusion: Our data indicate that citicoline can protect against malathion neurotoxic and genotoxic potential, possibly through antioxidant, anti-inflammatory activities, and restoring energy stores