The waves of yellow fever transmission in the Region of the Americas in 2016–2018 involved the largest number of human and epizootic cases to be reported in several decades. Yellow fever is a serious viral hemorrhagic disease that poses a challenge for health professionals. It requires early recognition of signs and symptoms, which are often nonspecific, and it can mimic other acute febrile syndromes. Early detection of suspected or confirmed cases, monitoring of vital signs, life support measures, and treatment of acute kidney failure continue to be the recommended strategies for case management. This report is the result of discussions among experienced specialists in the Americas on the clinical management of yellow fever patients, especially during outbreaks and epidemics, in the context of current medical and scientific evidence and taking into account the technical guidelines already available in the countries of the Region. It includes flowcharts for initially addressing patients with clinical suspicion of yellow fever and proposes a minimum package of laboratory tests that may be useful in contexts where resources are limited. In addition, it considers aspects of health system organization for dealing with yellow fever outbreaks and epidemics.