The merits of One Health have been thoroughly described in the literature, but how One Health operates in the United States federal system of government is rarely discussed or analyzed. Through a comparative case-study approach, this research explores how federalism, bureaucratic behavior, and institutional design in the United States may influence zoonotic disease outbreak detection and reporting, a key One Health activity. Using theoretical and empirical literature, as well as a survey/interview instrument for individuals directly involved in a past zoonotic disease outbreak, the impacts of governance are discussed. As predicted in the theoretical literature, empirical findings suggest that federalism, institutional design, and bureaucracy may play a role in facilitating or impeding zoonotic disease outbreak detection and reporting. Regulatory differences across states as well as compartmentalization of information within agencies may impede disease detection. However, the impact may not always be negative: bureaucracies can also be adaptive; federalism allows states important opportunities for innovation. While acknowledging there are many other factors that also matter in zoonotic disease detection and reporting, this research is one of the first attempts to raise awareness in the literature and stimulate discussion on the intersection of governance and One Health.