The pace and trajectory of global and local environmental changes are jeopardizing our health in numerous ways, among them exacerbating the risk of disease emergence and spread in both the community and the healthcare setting via healthcare-associated infections (HAIs). Factors such as climate change, widespread land alteration, and biodiversity loss underlie changing human–animal–environment interactions that drive disease vectors, pathogen spillover, and cross-species transmission of zoonoses. Climate change–associated extreme weather events also threaten critical healthcare infrastructure, infection prevention and control (IPC) efforts, and treatment continuity, adding to stress to strained systems and creating new areas of vulnerability. These dynamics increase the likelihood of developing antimicrobial resistance (AMR), vulnerability to HAIs, and high-consequence hospital-based disease transmission. Using a One Health approach to both human and animal health systems, we can become climate smart by re-examining impacts on and relationships with the environment. We can then work collaboratively to reduce and respond to the growing threat and burden of infectious diseases.