We present a framework to better understand and predict data-deficient and novel orthohantavirus traits based on three distinct orthohantavirus–rodent host groups: murid-borne, arvicoline-borne, and non-arvicoline cricetid-borne orthohantaviruses.Relative to other orthohantaviruses, cricetid orthohantaviruses often cause severe human disease, arvicoline orthohantaviruses cause mild disease, and murid orthohantavirus cause moderate disease.Murid orthohantaviruses are often transmitted through aerosolized excreta, arvicoline orthohantaviruses through aerosolized excreta and saliva, and cricetid orthohantaviruses through saliva.Murid and arvicoline orthohantaviruses generally have high host fidelity, but cricetid orthohantaviruses frequently spillover with possible multi-host systems.Our framework provides generalizable insight that can help inform public health and biosafety policy. Orthohantaviruses present a global public health threat; there are 58 distinct viruses currently recognized and case fatality of pathogenic orthohantaviruses ranges from <0.1% to 50%. An Old World versus New World dichotomy is frequently applied to distinguish human diseases caused by orthohantaviruses. However, this geographic grouping masks the importance of phylogeny and virus–host ecology in shaping orthohantavirus traits, especially since related arvicoline rodents and their orthohantaviruses are found in both regions. We argue that orthohantaviruses can be separated into three phylogenetically based rodent host groups with differences in key functional traits, including human disease, transmission route, and virus–host fidelity. This framework can help understand and predict traits of under-studied and newly discovered orthohantaviruses and guide public health and biosafety policy.