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Our goal in this study was to determine the effect of dietary supplementation with <i>Moringa oleifera</i> (<i>M. oleifera</i>), and <i>Azadirachta indica</i> (<i>A. indica</i>) leaves in mitigating the effects of chronic oxyfluorfen (OXY) toxicity on the health status, expressions of immune and antioxidant genes, and tissue morphological alterations in <i>Oreochromis niloticus</i>. In this study, we used 370 healthy <i>O. niloticus</i> (average weight = 25.35 ± 0.29 g). We used 70 fish to study the 96 h lethal concentration 50 (LC₅₀) of OXY. We assigned another 300 fish into six equal groups with five replicates (50 fish/group, 10 fish/replicate) to determine the chronic OXY toxicity for 60 days. The 96 h LC₅₀ of OXY for <i>O. niloticus</i> was 6.685 mg/L. Exposure to 1/10 96 h LC₅₀ of OXY (0.668 mg/L) had health impacts and pathological changes in the main tissues. In addition, the expressions of oxidant and immune genes were disrupted. Dietary supplementation with both <i>M. oleifera</i> and <i>A. indica</i> efficiently mitigated the toxic effects of OXY in the treated groups. Comparing the palliative efficiency of <i>M. oleifera</i> and <i>A. indica</i>, the results showed that <i>M. oleifera</i> was more potent in alleviating the toxic effects of OXY.