This study was conducted to evaluate the impact of human activities on the ecological health and food chain at the shores of four Nile Islands in Great Cairo including El-Qeratten, El-Waraq, El-Zamalek, and El-Manial. Water quality, bacteria, phytoplankton, benthic algae, zooplankton, macrobenthic invertebrates, and bony fishes were examined at each island shore over two seasons including the lowest and the highest flow (February and July 2020, respectively). The obtained results showed that the average values of most of the chemicals in Nile Island’s water were within the Egyptian water quality limits. Discriminant analysis of physicochemical factors revealed a similarity between El-Waraq and El-Qerateen and between El-Manial and El-Zamalek. El-Qeratten was the most polluted island. It has the highest total and fecal coliform bacteria count (3.155 and 3.050 Log MPN/100 mL, respectively). El-Zamalek shores have the highest phytoplankton (33,582 cells × 104 L−1) and zooplankton count (310,891 organisms × m−3) and phyto-biochemical values. Biochemical analysis of phytoplankton demonstrated the richness of the bulk by protein (> 85% of biomass), indicating that phytoplankton has a high nutritional value. Elevated zooplankton count was recorded at El-Zamalek, which coincided with the peak of phytoplankton abundance. Mollusca were the dominant macrobenthic invertebrates on most of the island’s shores. Bony fishes were represented by 27 species and two crustaceans. The levels of the metals in fish samples were compared with the food safety guideline endorsed by the World Health Organization and Food and Agriculture Organization (WHO/FAO) to evaluate the toxicity level.