This study assessed the effects of fluoride (FLO) on neurobehavioral function, brain oxidative status and inflammatory response, acetylcholinesterase activity, and histopathological picture in Nile tilapia (Oreochromis niloticus) with a mitigative trial using Artichoke (Cynara scolymus) leaf extract (AE). To achieve this, 240 O. niloticus fish (30 ± 1.5 g average initial weight) were distributed into four groups, each with four replicates in a 60-day feeding trial. A basal diet without supplements was given to the control group. A 300 mg/kg AE supplement was included in the 2nd group's basal diet (AE). A sub-lethal concentration of FLO (6.1 mg/L) was administered to the 3rd group of tilapias. Meanwhile, the last group was fed an AE-containing diet and exposed to FLO. The findings exhibited that supplementing AE to the O. niloticus diets significantly resolved the FLO-induced decrease in the frequency of middle swimming, feeding, and middle crossing. Additionally, AE food supplementation significantly (P < 0.05) attenuated the FLO-induced-aggression. The significant exhaustion in enzymatic and non-enzymatic antioxidant brain content documented in FLO-exposed fish was significantly reverted by AE incorporation into their diets. Also, cortisol, glucose, cholesterol, triglycerides, 8-OHdG, and MDA displayed detectable increases in FLO-exposed groups, but the level of brain acetylcholinesterase was significantly reduced. Pro-inflammatory cytokines (il-1β and tnf-α), apoptotic (caspase-3 and p53), and stress-related (hsp70) genes were noticeably elevated in the brains of fish treated with FLO, whereas the expression of anti-oxidative (sod and cat) genes was dramatically downregulated. Yet, incorporating AE in the diet repaired the alterations that FLO elicited in most of the indicators mentioned above. Further, AE dietary supplementation significantly minimized the FLO-induced histopathological alterations in the fish brain tissue. These findings suggested that AE would be an effective dietary supplement to lessen the harmful effects of FLO on the Nile tilapia's behavior and brain health.