The One Health concept underscores the interconnectedness of human, animal, and environmental health, necessitating an integrated, transdisciplinary approach to tackle contemporary health challenges. This perspective paper explores the pivotal role of genomics and bioinformatics in advancing One Health initiatives. By leveraging genomic technologies and bioinformatics tools, researchers can decode complex biological data, enabling comprehensive insights into pathogen evolution, transmission dynamics, and host-pathogen interactions across species and environments (or ecosystems). These insights are crucial for predicting and mitigating zoonotic disease outbreaks, understanding antimicrobial resistance patterns, and developing targeted interventions for health promotion and disease prevention. Furthermore, integrating genomic data with environmental and epidemiological information enhances the precision of public health responses. Here we discuss case studies demonstrating successful applications of genomics and bioinformatics in One Health contexts, such as including data integration, standardization, and ethical considerations in genomic research. By fostering collaboration among geneticists, bioinformaticians, epidemiologists, zoologists, and data scientists, the One Health approach can harness the full potential of genomics and bioinformatics to safeguard global health. This perspective underscores the necessity of continued investment in interdisciplinary education, research infrastructure, and policy frameworks to effectively employ these technologies in the service of a healthier planet.