Pesticide pollution of waterways is a significant problem that compromises the sustainability of aquaculture and harms the health of wild fish. The restoration potential of dietary white poplar leaves (WPL) during long-term hexaflumuron (HEX) exposure in Nile tilapia (Oreochromis niloticus) was studied for 60 days on growth, physiological, behavioral, gene expression, and histopathology assays. Two hundred fish (36.37 ± 0.15 g) were split into four equal groups, each having five replicates. The CONT (control) and WPL groups received basal diets fortified with 0 and 6 g WPL/kg, respectively, and were not treated with HEX. In contrast, the HEX and WPL + HEX groups received the same feeding as the CONT and WPL groups, respectively, and were treated with 0.72 mg/L HEX. The results showed that HEX exposure inhibited growth, induced behavioral alterations, and increased brain 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. However, the activity of acetylcholine esterase (AChE) did not significantly differ due to HEX exposure. HEX toxicity induced histopathological changes in the brain tissue, including pyknotic neurons, satellitosis, and gliosis. Additionally, the shortening of numerous secondary gill filaments and congested gill capillaries within some primary filaments was observed due to HEX exposure. The brain expression of the target of rapamycin, phosphoinositide 3-kinase, and V-akt murine thymoma viral oncogene homolog genes was upregulated, and the microtubule-associated protein light chain kinase 3 gene was downregulated due to HEX exposure. Upregulation of the ubiquitin-binding protein gene and downregulation of Beclin-1 and autophagy-related gene-12 were detected in the gills of the HEX fish with a high mortality rate (24%). Feeding on the WPL diet improved growth and behaviors and reduced brain 8-OHdG levels and mortality (10%). Furthermore, the WPL diet restored the histological picture of the brain and gill tissues and improved the autophagy process of the HEX-exposed fish. Collectively, the WPL diet could be used for the mitigation of the hazardous impacts of HEX toxicity in Nile tilapia. This could enhance our insight into the HEX toxicity mechanism and the protection offered by WPL.