This study evaluated the efficacy of integrating artichoke (Cynara scolymus) leaf extract (CSLE) into the Nile tilapia (Oreochromis niloticus) diet to mitigate fluoride (FLR) adverse effects on growth, immune components, renal and hepatic function, and the regulation of oxidative stress, inflammation, and apoptosis-related genes. A 60-day feeding experiment was conducted with 240 O. niloticus fish separated into four groups as follows: a control group (CON) fed on a basic diet, a CSLE group receiving 300 mg CSLE/kg via the diet, a FLR group exposed to 6.1 mg/L waterborne FLR, and a group receiving both CSLE and FLR. Fish exposed to FLR exhibited slower growth rates and poorer feed conversion compared to the control group. They also displayed signs of anemia, leukopenia, and elevated serum levels of renal injury indicators and liver enzymes. Consistent with a decrease in both non-enzymatic and enzymatic antioxidants, higher levels of hepatic lipid peroxidation products were observed. Exposure to FLR resulted in decreased serum lysozyme activity, nitric oxide, complement 3, IgM, total protein, globulin, and albumin levels. FLR induced multiple pathological perturbations in the spleen, liver, and kidneys, and increased the mRNA expression of splenic tumor necrosis factor-alpha, heat shock protein 70, interleukin-1 beta, tumor protein p53, and cysteine-aspartic acid protease 3 while reducing superoxide dismutase and catalase gene expression. However, the majority of FLR adverse effects were significantly reduced by adding 300 mg CSLE/ kg diet. Adding CSLE to O. niloticus' diet may reduce FLR's negative effects, making it a beneficial aquafeed.