Microplastics contamination is widespread in the environment leading to the exposure of both humans and other biota. While most studies overemphasize direct toxicity of microplastics, particle concentrations, characteristics and exposure conditions being used in these assays needs to be taken into consideration. For instance, toxicity assays that use concentrations over 100,000 times higher than those expected in the environment have limited practical relevance. Thus, adverse effects on animal and human health of current environmental concentrations are identified as a knowledge gap. Conversely, this does not suggest the lack of any significant effects of microplastics on a global scale. The One Health approach provides a novel perspective focused on the intersection of different areas, namely animal, human, and environmental health. This review provides a One Health transdisciplinary approach to microplastics, addressing indirect effects beyond simple toxicological effects. Microplastics can, theoretically, change the abiotic properties of matrices (e.g., soil permeability) and interfere with essential ecosystem functions affecting ecosystem services (e.g., biogeochemical processes) that can in turn impact human health. The gathered information suggests that more research is needed to clarify direct and indirect effects of microplastics on One Health under environmentally relevant conditions, presenting detailed knowledge gaps. Display omitted •Microplastics threaten multiple systems from organism to population and processes.•Microplastics pose interconnected risks to environmental, human, and animal health.•A transdisciplinary approach under One Health is recommended.•Greater collaboration between experts of different fields is required.