High fluoride (FL) concentration in many areas of the world is of great concern. It poses a threat to aquatic life. Therefore, the current study was operated to scrutinize the efficiency of Silybum marianum (SM) and/or coenzyme Q10 (CQ10) dietary supplementation to rescue FL negative effects on the growth, hematological indicators, liver and kidney function, serum protein profile, innate immune parameters, oxidative status, vital organ architecture, and disease resistance to Aeromonas sobria. Two hundred and forty healthy Clarias gariepinus fish were alienated into eight groups in triplicate. The control group was fed a non-supplemented basal diet. The SM, CQ10, and SM + CQ10 groups were fed a basal diet fortified with 10 g SM/kg diet, 40 mg CQ10/kg diet, or SM + CQ10, respectively. The FL group was exposed to 73.45 mg FL/L water. The FL + SM, FL + CQ10, and FL + SM + CQ10 were exposed to FL concomitantly with SM, CQ10, and SM + CQ10, respectively. The experiment continued for 60 successive days. The results showed lower weight gain and specific growth rate but higher hepatosomtic index in the FL-exposed fish. An obvious leukopenic and anemic condition was detected. Also, a significant increase in the serum levels of hepatic enzymes and kidney damage products was apparent in FL-exposed fish. Nevertheless, exhaustion of the non-enzymatic and enzymatic antioxidants but elevated lipid peroxidation product (MDA) was noted. The FL exposure exhausted lysozyme activity, complement 3, nitric oxide, total proteins, albumin, and γ globulin contents in the serum of C. gariepinus. Moreover, diverse pathological alterations were detected in the liver, kidney, and spleen. After 14 days of A. sobria challenge, the relative survival rate percentage was significantly reduced in FL-exposed fish. On the contrary, the SM and/or CQ10 addition significantly reduced most FL-associated negative impacts. Conclusively, SM and/or CQ10 dietary supplements could be beneficial for alleviating FL deleterious impacts, thus affording advantageous aqua feed additive for C. gariepinus.