This study explored the combined influence of tank color, stocking density, and gender on Tilapia zillii's performance and well‐being. In this 120‐day trial, 320 T. zillii, each initially weighing 10.0 ± 0.1 g/fish, were distributed among 24 tanks. The experiment included eight distinct treatment combinations, varying tank color (blue and green), stocking density (10 and 30 fish/m3) and sex (monosexual and mixed). The results showed that blue tanks improved specific growth rate and condition factor, while green tanks were better for feed utilization. Density at 30 fish/m3 showed the highest mean values of final body weight and total length, weight gain (WG), and gain length. Mono‐sex outperformed mixed‐sex ones in WG and daily growth. Interactions between color, density and sex were significant, affecting growth and feed utilization. Green tanks were best for protein profiles, while blue tanks excelled in glucose. A density of 10 fish/m3 yielded the highest protein profiles, and mono‐sex fish had higher protein profiles. For lipid profiles, green tanks were superior, and density affected lipid profiles. Mixed‐sex populations were best for certain lipid profile parameters. Interactions between these factors also played a significant role, making the biochemical profiles of T. zillii a complex interplay of various factors. The results explored that tank color, fish density and sex influence the activity of nonspecific immune enzymes in the liver of T. zillii. Blue tanks and lower fish density led to higher nonspecific immune enzymes, while mono‐sex fish exhibited more significant nonspecific immune enzymes. Complex interactions between these factors also influenced nonspecific immune enzyme activities. Blue tanks increased malondialdehyde (MDA) levels, while green tanks raised glutathione S‐transferases (GST) and catalase (CAT) levels. Lower fish density led to higher MDA, while higher density increased GST and CAT. Mono‐sex fish had more MDA and GST, while mixed‐sex fish showed greater CAT levels. Complex interactions among these factors affected the antioxidant levels in T. zillii. In summary, our study suggests that rearing T. zillii in green tanks at higher densities (30 fish/m3) and in mono‐sex conditions yields the best results in terms of growth and overall performance.