The study assessed heavy metals (Cd, Cu, Fe, Mn, Pb and Zn) and physico-chemical parameters in water, sediments and fish from an endorheic lake (Lake Chilwa) in Malawi. It was observed that pH (max. 9.7), EC (max. 2936 μS/cm), TDS (max. 2119 mg/L), NO3− (max. 6.6 mg/L) and PO43− (max. 1.3 mg/L) were higher in the dry season than in the rainy season. Pb was not detected in all samples. However, the rest of heavy metals were detected with significant values of Mn and Cu in fish (Mn: 0.015–1.18 mg/kg dry weight, dw; Cu: 0.41–0.92 mg/kg dw) and sediment (Mn: 2.25–10.66 mg/kg dw; Cu: n.d–1.63 mg/kg dw). The concentrations of heavy metals in fish samples were below the maximum limits for edible fish recommended by Food and Agriculture Organization/World Health Organization: Cd (0.1 mg/kg), Cu (3 mg/kg), Fe (43 mg/kg), Pb (0.2 mg/kg), Mn (2–9 mg/kg) and Zn (60 mg/kg). The calculated target hazard quotients (ranged from 0.001 to 1.07) indicated no human risks from fish consumption. Furthermore, dry season values for Mn, Cu and Zn in sediments were significantly higher (p < 0.05) than those of the rainy season. Conversely, Fe in sediments was significantly higher (p < 0.05) in the rainy season than in the dry season. The use of fertilizer and indiscriminate disposal of metal products contributes to the observed levels. This calls for reinforcement of suitable agricultural and waste management practices in the study area.