Contamination of the aquatic bodies with pesticides is a serious issue that hinders the aquaculture industry worldwide. Preventing aquatic pollution is a challenge, and finding eco-friendly strategies could help to overcome such a problem. Herein, we studied the antagonistic potential of dietary fortification of white poplar (Populus alba; PA) leaf powder against chronic hexaflumuron (HX) toxicity in Nile tilapia (Oreochromis niloticus). Fish (n = 200; 36.20 ± 1.55 g) were eventually grouped into four groups with five replicates and kept for 60 days. The C (control) and PA groups were fed basal diets fortified with 0 and 6 g PA/kg diet, respectively, without toxicant exposure. Additionally, the HX and PA + HX groups were exposed to 1/10 of 96-h lethal concentration 50 (96-h LC50) of HX (0.72 mg/L) and given the same diets as those of the C and PA groups, respectively. The biochemical, immune-antioxidant, survival, splenic gene expression, and tissue microstructure were assessed at the end of the exposure time. The outcomes of this research showed that exposure to HX resulted in biochemical disorders (elevated blood glucose, cortisol, alanine aminotransferase, aspartate aminotransferase, and creatinine) in Nile tilapia. Immune suppression (lowered complement 3 and immunoglobulin M) and oxidative stress (lowered superoxide dismutase and catalase activity and higher malondialdehyde) were consequences of HX toxicity. The splenic expression of nuclear factor-kappa β65, kelch-like ECH-associated protein 1, and heme oxygenase-1 was down-regulated by HX exposure. Various pathological changes were noted as consequences of HX exposure in the liver, kidney, and spleen tissues. By feeding on the PA diet, the fish survivability was increased (90%) compared to the non-fed group (76%). Additionally, the biochemical disorders were modulated, and immune responses were enhanced due to PA feeding. Amelioration of the oxidative stress condition (by improving the antioxidant enzyme activity and lowering malondialdehyde) and the immune gene expression were noticed when the HX-exposed Nile tilapia were fed on the PA diet. A noticeable soothing effect was noticed by feeding on the PA diet against the pathological changes in the Nile tilapia tissues. Overall, feeding on a 6 g PA/kg diet ameliorates the detrimental consequences of HX toxicity in Nile tilapia.