Brain injury initiates a neuroinflammatory cascade that contributes to substantial neuronal damage. Administration of lipopolysaccharide (LPS) impaired antioxidant mechanisms, increased peroxidation and impaired mitochondrial redox activity causing brain inflammation as well as neuronal damage and impairment of brain monoamines. Apigenin gathered extensive attention in recent years because of its chemopreventive, antioxidant and antiinflammatory effects. This study aimed to evaluate the impact of apigenin in LPS induced brain injury in experimental rats and to evaluate its role in monoamines regulation as well as DNA damage reduction. Forty male albino rats were used in this study, divided into four groups (control, apigenin, LPS and treated groups). Brain malondialdehyde (MDA), brain nitric oxide (NO) and serum paraoxnase activity (PON-1) were estimated colorimeterically. DNA damage was evaluated by comet assay method, in addition to brain monoamines assessment by HPLC. Histopathological and Immunohistochemistry of cyclooxygenases (COX-1, COX-2) were also performed. The data showed that lipopolysaccharide significantly increased brain MDA, NO and monoamines concomitant with a reduction in PON-1. Contrarily, apigenin supplementation improved these values in treated group. The present study provides insights into the design of flavonoid with optimal neuroprotective activities.