Although healthy plants are vital to human and animal health, plant health is often overlooked in the One Health literature. Plants provide over 80% of the food consumed by humans and are the primary source of nutrition for livestock. However, plant diseases and pests often threaten the availability and safety of plants for human and animal consumption. Global yield losses of important staple crops can range up to 30% and hundreds of billions of dollars in lost food production. To demonstrate the complex interrelationships between plants and public health, we present four case studies on plant health issues directly tied to food safety and/or security, and how a One Health approach influences the perception and mitigation of these issues. Plant pathogens affect food availability and consequently food security through reductions in yield and plant mortality as shown through the first case study of banana Xanthomonas wilt in East and Central Africa. Case studies 2, 3 and 4 highlight ways in which the safety of plant-based foods can also be compromised. Case study 2 describes the role of mycotoxin-producing plant-colonizing fungi in human and animal disease and examines lessons learned from outbreaks of aflatoxicosis in Kenya. Plants may also serve as vectors of human pathogens as seen in case study 3, with an example of Escherichia coli (E. coli) contamination of lettuce in North America. Finally, case study 4 focuses on the use of pesticides in Suriname, a complex issue intimately tied to food security though protection of crops from diseases and pests, while also a food safety issue through misuse. These cases from around the world in low to high income countries point to the need for interdisciplinary teams to solve complex plant health problems. Through these case studies, we examine challenges and opportunities moving forward for mitigating negative public health consequences and ensuring health equity. Advances in surveillance technology and functional and streamlined workflow, from data collection, analyses, risk assessment, reporting, and information sharing are needed to improve the response to emergence and spread of plant-related pathogens and pests. Our case studies point to the importance of collaboration in responses to plant health issues that may become public health emergencies and the value of the One Health approach in ensuring food safety and food security for the global population.