Ochratoxin A (OTA) is one of the most abundant mycotoxins in fish diets and cause a severe loss in fish body weight and suppression of immune responses. The present study was conducted to evaluate the ability of dietary active yeast (Saccharomyces cerevisiae) to alleviate the drastic effect of OTA on Nile tilapia (Oreochromis niloticus) fingerlings (23.39 ± 0.16 g). Six experimental treatments were applied in 18 circular fiberglass tanks (0.5 m³;three tanks per treatment). The treatments were: control, yeast supplementation (0.5 g kg^-1 diets), low OTA dose (LOTA; 80 µg kg^-1 bwt), high OTA dose (HOTA; 160 µg kg^-1 bwt), LOTA plus yeast and HOTA plus yeast. The OTA doses applied as a single dose on the first day of the experiment by stomach intubation, then the experiment lasted for 8 weeks. All treatments were vaccinated with Aeromonas hydrophila bacterin after one month of OTA treatments. Results indicated that OTA caused a significant reduction in final bwt, weight gain, average daily gain and significant deterioration of feed conversion ratio (FCR) in a dose dependent manner compared to the control group. The survival rate decreased by 10 and 26.67% with low and high OTA doses, respectively than the control group. WBCs, lymphocytes, phagocytic activity, phagocytic index, total protein, albumin and globulin decreased significantly with both of OTA doses. Antibody titer was reduced significantly with OTA treatments in a dose dependent manner and the significant effect of OTA in high dose appeared after two weeks of vaccination compared to control. The histology of liver and posterior kidney revealed that there was an increase in the incidence and severity of histopathological lesions in a dose dependent manner. However, dietary yeast alone improved significantly growth performance, survival rate, FCR, and stimulated both innate and adaptive immune responses, also, didn't show histological changes in tested organs. The yeast supplementation to OTA treated fish overcomes successfully the drastic effect of OTA on the all previous mentioned parameters. In conclusion, OTA causes interruption of Nile tilapia performance, suppression of innate and adaptive immune response, whereas, active yeast supplementation showed a protective effect of active yeast against the OTA toxicity.