This study explored the effect of Silybum marianum (SLM) and/or co-enzyme Q10 (Co-Q10) dietary supplementation on the health of nickel (Ni)-exposed Nile tilapia (Oreochromis niloticus). For this purpose, 240 fish were divided into eight groups (30 fish/group). Four groups were reared in non-contaminated water and fed a non-supplemented basal diet, 10 g SLM /kg diet, 40 mg Co-Q10 mg/kg diet, and SLM+Co-Q10 containing diet. The other four groups were exposed to Ni (3.6 mg/L water) and fed a basal diet, SLM, Co-Q10, or SLM+Co-Q10 supplemented diets. After 40 days, the growth performance indicators and serum biochemical indices were estimated. Moreover, the mRNA levels of some immune-related genes were measured. Furthermore, the Ni content was estimated in various fish tissues. The histological architectures of hepatic, renal, and splenic tissues were examined. A 14 days challenge experiment was performed to assess the fish resistance to Pseudomonas aeruginosa. The results displayed that SLM and/or Co-Q10 significantly corrected the Ni-induced anemic and leukopenic conditions. In addition, SLM and/or Co-Q10 significantly mitigated the impaired growth and hepatic, splenic, and renal dysfunctions caused by Ni exposure. Also, exhausted immune and antioxidant components resulting from Ni exposure were significantly reestablished by SLM and/or Co-Q10. In addition, the reduced resistance of Ni-exposed fish to the P. aeruginosa infection was significantly reestablished in SLM and/or Co-Q10 groups. Moreover, SLM and/or Co-Q10 significantly suppressed the Ni-induced increase in serum malondialdehyde content and Ni accumulation in different organs. Additionally, the Ni-induced upregulation of the mRNA levels of tumor necrosis factor-alpha, interleukin 1β, and CC chemokines but down-regulation of CXC and interleukin 10 mRNA levels were corrected in SLM and/or Co-Q10 groups. Overall, SLM and/or Co-Q10 may be beneficial dietary supplements for mitigating Ni's harmful effects in O. niloticus and improving growth, thereby providing a good aqua feed additive for cultured freshwater fish.