Epilepsy, a chronic neurological disorder affecting over 65 million individuals globally, is characterized by recurrent seizures that disrupt neuronal activity, often leading to cognitive and behavioral impairments. Emerging research underscores the pivotal role of NADPH oxidases (NOXs), particularly NOX2, in the pathophysiology of epilepsy. These enzymes catalyze the production of reactive oxygen species (ROS), which amplify neuronal hyperexcitability, mitochondrial dysfunction, and neuroinflammation, thereby establishing a self-sustaining pathological feedback loop that drives epileptogenesis and progression to chronic epilepsy. Preclinical and clinical studies have demonstrated pronounced upregulation of NOX isoforms (particularly NOX2) following seizures and during chronic epilepsy. NOX-derived ROS have been directly implicated in neuronal injury, increased seizure susceptibility, and hippocampal sclerosis, which are hallmarks of temporal lobe epilepsy. Therapeutic targeting of NOX enzymes represents a promising avenue for epilepsy management. NOX inhibitors, such as apocynin and the NOX2-specific peptide inhibitor gp91ds-tat, have demonstrated efficacy in preclinical models, effectively attenuating seizure activity, mitigating neuronal damage, and enhancing cognitive outcomes. These agents also preserve the integrity of the blood-brain barrier and suppress neuroinflammatory responses, both of which are critical contributors to epileptogenesis. Nevertheless, challenges persist, including the necessity for isoform-specific targeting and efficient blood-brain barrier penetration, which must be addressed to optimize therapeutic efficacy. This chapter elucidates the central role of NOXs in the pathogenesis of epilepsy, advocating the advancement of NOX-targeted therapies as a means to ameliorate disease outcomes and alleviate the long-term burden of this debilitating condition.