Egyptian coastal lakes represent about 25 % of the Mediterranean total wetlands. Four of the coastal lakes are located north of the Nile Delta and are known as the Northern Delta Lakes. They are severely environmentally degraded and are considered vulnerable to the impacts of climate change, in particular the expected sea level rise. Lake Manzala lies on the eastern north coast of Egypt and is considered as the largest Egyptian coastal lake. Economically, Lake Manzala is considered as one of the most valuable fish sources in Egypt. The water quality status of the lake has been degraded due to the progressive increase in industrial, municipal, and agricultural wastewater discharge. In this work, a hydrodynamic and water quality model for Lake Manzala was developed, under the limitation of hydrological data, which prevented model validation, using MIKE21 modeling system. The proposed model was calibrated with observed data for 1 year (August 2010–July 2011). Typical records at five stations for water levels were used, while the water quality data were collected from 11 field stations. The model results show good agreement with the observed water depth, water temperature, and salinity records. The values of average absolute error, for all stations, were about 0.06 m and 0.56 °C for water depth and water temperature, respectively. In the following, the calibrated model is going to be used to investigate the impacts of future climatic changes on hydrodynamic and water quality characteristics of the lake. Moreover, this developed model will be used as a management tool to examine different enhancement water quality scenarios for the lake.