A study was conducted to find out the possible reasons of fish killing at the Jeddah Coast, the Red Sea, Saudi Arabia. There are many factors for a sudden fish die-off in a water body such as toxic discharges, low dissolved oxygen (DO), temperature, salinity, pH, ammonia, turbidity, pesticides, toxins, and diseases. The study was carried out to find out the reasons of sudden fish killing. Therefore, physico-chemical and biological parameters, and postmortem, especially the gills and gut content of dead fishes were studied. The dead Tilapia tilapia (Tilapia), Chanos chano (Milkfish) and Parapriacanthus ransonneti (Glassfish) were found with wide mouth opened, skin with huge mucous and a bent back head, flared gills lesion and reddish sanguinary. The water temperature (°C), DO, salinity and pH varied from 24.8 to 26.2 (°C), 0.10 to 0.35 mg/L, 7.41 to 18.77 ppt and 7.31 to 7.64, respectively. Water column microalgal cell abundance varied from 78×103 to 147×103cells/L, with an average of 97.2×103 cells/L. The abundance of microalgae in gut was 137.30×103, 105.30×103 and 204.14×103 cells/g of gut of Tilapia, milkfish and glassfish, respectively. In gut, microalgae of Bacillariophyceae were 60, 81 and 61% among total microalgae in gut content of Tilapia, Milkfish and Glassfish, respectively. There was no microalga on gills. The salinity was 50 to 79% lower than that of the normal salinity of the Red Sea due to rain on previous day of fish killing. Sudden decrease of salinity and nearly zero DO concentration might be the reasons of killing fish by creating osmotically imbalance and suffocation of fishes. Additionally, due to low pH, huge mucous covered the gills filaments which might have created difficulties for respiration. Thus, the fish killing incident might have occurred by synergetic effects of different physico-chemical factors.