Water resources in good quality guarantee the primary condition for the maintenance and development of the natural ecosystem and human society. Water quality status and health risk of the lake water bodies in the national nature reserve, the Yamdrok-tso basin, in the southern Tibetan Plateau are assessed by 25 water parameters including 12 heavy metal(loid)s. Results reveal that the lake water bodies possess relatively high pH (9.68), high concentrations of F (1.66 mg/L), Cu (13.92 μg/L), As (41.60 μg/L), Pb (26.69 μg/L), and U (19.53 μg/L), and a low value of dissolved oxygen (19.30%). The pollution indices (heavy metal pollution index of 0.88–22.88, heavy metal evaluation index of 0.18–3.75, and the degree of contamination of −8.82 to −5.25) demonstrate that the lake water bodies are in a low pollution level with respect to heavy metal(loid)s. The evaluation of water quality based on the fuzzy comprehensive assessment method suggests that 75.56% of the water samples meet the regulation of the China National Standard for water resources in national nature reserves. Health risk assessment shows that potential hazards exist on this region when the residents under long-term exposure to the lake water through oral and dermal pathways, of which children and adults are mostly exposed to As and F for non-carcinogenic and As for carcinogenic risks, especially for children. Results of this study contribute to targeted water resources management in the national nature reserves.