Nanoscale matter has unique attributes that potentiate their widespread application from biomedicine, engineering, food, cosmetics, sensing, to energy. Due to the rapid industrialization of engineered nanomaterials (ENMs) as a result of increasing consumer interests, more ENMs will be released into the environment, greatly increasing the probability of their contact with humans. Once these ENMs enter the human body or an ecosystem, they may initiate various biochemical responses in unprecedented ways, thus raising important concerns in regard to their effects on human health and the ecosystem. Here, the shifts in the intricate metabolic pathways instigated by ENMs are highlighted and those altered metabolic changes are extrapolated for the elucidation of environmental health and risk assessment. Furthermore, the toxico-metabolomics knowledge of ENMs provides the opportunity to design novel nanomedicine with high efficacies by capitalizing on their abilities to rewire metabolic networks for the treatment of diseases.