One Health is the concept that human, animal and environmental health are interconnected. Outbreaks of zoonoses, vector-borne diseases, or those related to contamination of the environment are best investigated using a multi-disciplinary One Health approach. Outbreaks of emerging zoonotic infectious diseases where infections in multiple species – from humans, to livestock, to wildlife – may only be well understood if a One Health approach is used. Investigations of spillover events – where a human or new animal species has been infected by a virus, bacteria, or parasite – also require a One Health approach. Beyond infectious diseases, the environment can be contaminated by heavy metals, industrial pollution and other toxins, which can pose a risk to both human and animal health. In order to protect human and animal health from these threats, One Health approaches can be integrated into outbreak investigations and spillover investigations to improve our mechanistic understanding of their proximal and distal causes leading to insights about how they can be prevented.