Arsenic (As) is a widespread environmental pollutant that poses serious risks to aquatic organisms, particularly affecting neurological health through oxidative damage, endoplasmic reticulum (ER) stress, and apoptosis. Natural bioactive compounds such as genistein (GNT), a soy-derived isoflavone, have shown potential in counteracting heavy metal-induced toxicity due to their antioxidant and anti-apoptotic activities. This study evaluated the neuroprotective effects of dietary GNT (500 mg/kg) in Nile tilapia (Oreochromis niloticus) exposed to 10 µg/L As for 60 days. Arsenic exposure significantly impaired neurobehavioral performance, including reduced ingestive, swimming behaviors, and aggression. Dietary supplementation with GNT effectively ameliorated these behavioral disturbances. At the biochemical level, As exposure decreased the activities of key brain antioxidants, superoxide dismutase, catalase, and reduced glutathione, while increasing malondialdehyde (MDA). Genistein reversed these oxidative imbalances, restoring antioxidant enzyme activities and reducing MDA levels. Furthermore, GNT significantly upregulated brain acetylcholinesterase content and modulated the expression of genes associated with endoplasmic reticulum (ER) stress and apoptosis. Specifically, GNT reversed As-induced dysregulation in the expression of jnk, chop, eif-2a, xbp-1, ire-1a, atf-6, bip, perk, caspase-3, bax, and bcl-2, indicating its role in mitigating ER stress and apoptotic signaling. Histopathological examination confirmed the protective role of GNT against As-induced brain tissue damage. In conclusion, GNT supplementation offers promising neuroprotection against As-induced toxicity via the modulation of oxidative stress, ER stress, and apoptosis in Nile tilapia.