This study evaluated levels and seasonal patterns of lead (Pb) and cadmium (Cd) in sediment, water, and mudskippers (Periophthalmus argentilineatus) from urban rivers in Dar es Salaam, Tanzania. The samples were seasonally collected from 15 locations, treated as appropriate, and analyzed instrumentally. The study intended to establish contamination levels, identify hotspots, and assess ecological and human health risks. The results indicated that Cd concentrations were lower than Pb in all the sample matrices. In water samples, Pb levels (0.7 to 24.0 mg/L, n = 30, mean = 7.2 ± 6.5) were higher than both the World Health Organization (WHO) and the Tanzanian Bureau of Standards limits, whereas Cd was below the detection limit. In sediment samples, both the Pb concentrations (9.0 to 159.3 mg/kg, n = 30, mean = 44.7 ± 36.6) and the Cd concentrations (0.03 to 0.82 mg/kg, n = 30, mean = 0.24 ± 0.14) exceeded sediment quality guidelines for the protection of aquatic life. The mudskipper samples contained levels below the Food and Agriculture Organization (FAO) and WHO maximum permissible limits. This indicated that they were safe for human consumption. Metal concentrations in water and sediments were lower during the dry season than in the wet season, probably owing to contaminated runoff from land-use practices during the wet season, whereas the mudskipper samples showed the opposite pattern. Determination of the potential contamination index (PCI) in samples enabled the identification of two hotspots that may need intervention. Evaluation of chronic daily intake (CDI), hazard quotient (HQ), and hazard index (HI) implied minimal health risks. Contamination of the rivers by these toxic metals, be it in low concentrations, is an issue of concern.