Lake Burullus represents an economically important brackishwater coastal lagoon in Egypt, due to its rich fishery resources. In addition to the remains of agricultural wastes, the lake is exposed to many kinds of chemical and biological pollutants that are disposed into it. So, the study was carried out on three sectors in the lake. Western sector of the lake where agricultural drainage was discharged, eastern sector where agricultural and industrial effluents was entered, and middle sector where the least pollution was occurred among them. The present study was controlled to assess the harmful effects of heavy metals on the biochemical and antioxidant defense system in Nile tilapia collected from three sectors. The studied heavy metals in gills, liver, and muscles of the Nile tilapia (Oreochromis niloticus) collected from the eastern and western sectors of the lake was much higher than that of fish collected from middle sector. Biochemical profile and antioxidant defense system of Nile tilapia were significantly (P<0.05) higher in fish collected from western and eastern sectors during summer and winter seasons compared to the middle sector. The results obtained from the present study also revealed that the meat quality of the collected fish from middle sector was more superior to those of fish collected from the eastern and western sectors of the lake. The study also indicates that the alterations in the biochemistry profile and antioxidant defense system of Nile tilapia can be used as biomarkers of metal pollution for monitoring aquatic life.