Microplastics (MPs) have received significant attention due to their harmful impact on fish production. This research investigated the protective effects of the yeast, Saccharomyces cerevisiae (Sc) against MPs-induced toxicity in the Nile tilapia, focusing on growth performance, fed utilization, gene expression (IGF-1, IGF-2, and GH), biochemical markers, and immune responses. A total of 270 fingerlings were divided into nine groups; the control group received a basal diet, while the other groups were exposed to varying concentrations of Sc (2 and 4g/ kg) and MPs (10 and 50mg/ L). MPs exposure negatively impacted growth performance, feed efficiency, survival rates, and body composition. Nevertheless, dietary inclusion of Sc notably improved these parameters, particularly in groups receiving 4g/ kg Sc. Exposure to MPs led to down-regulation of gene expression in the liver and gills, whereas Sc supplementation increased gene expression, especially in the liver. Biochemical analysis showed increased levels of AST and ALP in most groups, with kidney function tests revealing elevated blood urea and serum creatinine. Additionally, cholesterol levels were significantly higher in group receiving 4g/ kg Sc. Immune response assessment indicated elevated lysozyme and antiprotease activities, with the highest levels observed in groups treated with 10mg/ L MPs plus 4g/ kg Sc and 50mg/ L MPs plus 4g/ kg Sc. The results suggest that Saccharomyces cerevisiae, particularly at a concentration of 4g/ kg, acts as a beneficial probiotic that alleviates MPs toxicity, enhancing growth, gene expression, and immune responses in the Nile tilapia.