MANZALA Lake, the largest Egyptian northern lake, suffers from continuous deterioration as it receives huge amounts of different wastes. This study evaluated the abiotic and biotic conditions of the lake water (e.g., physicochemical variables, bacterial communities, and phytoplankton structures and their biochemical contents) from 11 sites along the lake in winter and summer 2020. The results revealed that the increase in phytoplankton densities and chlorophyll (a) in winter combined with increased nutrient contents. The highest concentrations of the biochemical contents of phytoplankton and the highest enumerations of bacterial indicators were recorded during summer. The sites close to the inlets of drains recorded a complete depletion of oxygen and a high ammonia content. The highest phytoplankton standing crop was recorded in the middle sector of the lake. Despite the efforts of the Egyptian government to rehabilitate Manzala Lake since 2017, the results showed an increase in pollution levels at various sites and the continued deterioration of the lake's ecological status. These results confirm the importance of increasing the efforts to restore the environmental health status of the lake, primarily by treating wastewater before it is discharged into the lake.