Lake Qarun is Egypt's third-biggest lake, with an enclosed water system. The only source of water intake in the lake is drainage water, while evaporation is the only outflow path. This source of pollution affects water and fish; therefore, it threatens food security, which is an essential multi-dimensional goal in the United Nations 2030 Agenda. Fish contaminated with heavy metals are unsafe for humans and may cause serious health problems. Hence, this study aimed to determine the seasonality of heavy metals contents in the surface water and tissues of fishes (Tilapia zillii and Mugil cephalus) to assess and match the different exposure routes and possible health risks related to heavy metals in Lake Qarun. Various indices were estimated in the present research, based on the levels of heavy metals in the surface water and fish of the lake including heavy metal evaluation index (HMEI), chronic daily intake (CDI), target hazard quotient (THQ), hazard index (HI), carcinogenic health hazard (CHH), metal pollution index (MPI), estimated daily intake of heavy metals (EDI), and target cancer risk (TR). Additionally, the inverse distance weighting (IDW) technique from GIS was used to map the spatial distribution of the heavy metals in the lake during the seasons of summer and winter. Results revealed that higher metal contents were recorded in surface water and fish tissue samples during summer compared to winter. Moreover, the highest metal concentrations were reported in the eastern section of the lake. No health hazards were detected, either persuaded by the ingestion or dermal contact of Lake Qarun surface waters, while serious health hazards were recorded from the ingestion of both fish (especially T. zillii) during the study. Therefore, the residents and fishermen in the study area should be forewarned since they are highly exposed to all routes of health hazards related to heavy metals contents in the lake. In addition, an immediate consideration is necessary to avoid the continuous abuse of the lake by untreated sewage and agricultural effluents that limit the potential of Lake Qarun.