The environmental pollution of lake systems due to anthropogenic factors is of growing concern worldwide. Manzala Lake is the largest northern coastal-deltaic lakes of Egypt and has socioeconomic impacts. In this study, the concentrations and origins of seven heavy metals (HMs) and the organic content in the Manzala Lake sediments were explored during the winter and summer. The concentration of the HMs and the organic content were quantified using inductively coupled plasma and loss-on-ignition techniques. Pearson’s correlation coefficient (PCC) and principal component analysis (PCA) were applied to evaluate the sources of the metals in the sediments. The HMs and organic matter were enriched during the winter season. The average concentrations of the HMs in the sediments conformed to the following sequence: Fe (14.13) > Mn (0.8) > Cu (0.11) > Zn (0.11) > Ni (0.06) > Pb (0.5) > Cd (0.002) (mg/kg). Sediment quality protocols showed that Mn, Cd, Cu, and Ni pose a significant threat to the aquatic environment in Manzala Lake. The geoaccumulation index (I_geo) values indicated pollution of the sediments with most metals, excluding Fe and Ni. The periodic mean I_geo pollution level followed the sequence Cd > Cu > Zn > Mn > Pb > Ni > Fe. The greatest pollution load index noted during the winter season was principally induced by Cd and Cu. The overall ecological risk index was moderate, with Cd being the most prominent HM. PCA combined with PCC showed that the HM enrichments in the southern (Bahr Al-Baqar Drain [S1], Bashteer [S3], Legan [S5], and Al-Ginka [S8]) and the extreme northeastern (El-Qapouti [S6]) parts of Manzala Lake sediments were mainly due to the discharge from different drains (industrial, agricultural, and municipal wastes) and the industrial region in Port Said, respectively. The lower HM concentrations from the extreme northern parts (Al-Boghaz [S2], Al-Temsah [S4], Al-Hamra [S7], and Al-Kowar [S9]) were due to their isolation from urban areas compared with the other localities. Extensive waste disposal was responsible for the HM pollution in the Manzala Lake sediments. Advanced treatment technologies and monitoring of the pollution in the water and sediments of Manzala Lake are required to decrease the accumulation of the heavy metals.