Understanding the occurrence, behavior, and fate of potentially toxic elements (PTEs) in the substrate-mushroom-human nexus is critical for assessing and mitigating their human health risks. In this review, we (1) summarized the nature, sources, and biogeochemical behavior of PTEs in the substrate-mushroom systems; (2) discussed the occurrence, exposure, and human health risks of PTEs in mushrooms with emphasis on African geological hotspots such as metalliferous and highly mineralized substrates; (3) developed a 10-step conceptual framework for identifying, assessing, and mitigating the human health risks of PTEs in mushrooms, and highlight future directions. High human exposure risks potentially exist in Africa due to the following: (1) widespread consumption of mushrooms from various metalliferrous and highly mineralized substrates such as serpentines and mine waste dumps, (2) inadequate and poorly enforced environmental health and food safety regulations and policies, (3) limited environmental and human health monitoring data, and (4) potential synergistic interactions among PTEs in mushrooms and human health stressors such as a high burden of human diseases and infections. Although the human health effects of individual PTEs are well known, scientific evidence linking human health risk to PTEs in mushrooms remains weak. A framework for risk assessment and mitigation, and future research directions are recommended.