Due to the limited water resources for fish culturing, fish farming using wastewater has been adopted in many countries. Therefore, fish are in continuous exposure to these pollutants. Considering fish, a bio-indicator model to monitor the aquatic pollution, this study was undertaken to evaluate a general fish health indicators at the cellular and molecular levels in cultured Nile tilapia (Oreochromis niloticus) using wastewater effluents as their primary water source over three sites known for their industrial pollution as highly polluted sites (S1), moderately polluted (S2) and a putative control deemed low in contaminants (reference site, RS). The impact of wastewater was assessed in Nile tilapia and results revealed a significant increase in innate immune, oxidant/antioxidant parameters and serum biochemical parameters; mostly in fish captured from (S1) than others. Liver tumour necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) mRNA levels were significantly increased in fish from contaminated sites compared with those from the unpolluted site. Phenolic compounds were detected in water and liver tissue of fish captured from the highly polluted site. The principal component analysis (PCA) score plots for these parameters revealed that the groupings were based on high percentage of the explained variance in all cases (60% for control, 60% for site 1 and 40% for site 2). The current findings suggested a correlation between biomarkers response and wastewater exposure as stressors. Besides, the assessed multiple general health indicators give potential insights for Nile tilapia adaptive pattern and monitoring of pollution of freshwater ecosystems.