Tularemia is a rare nationally notifiable zoonosis, caused by the tier-1 select agent Francisella tularensis, that has been reported from all U.S. states except Hawaii. Clinical manifestations typically include fever and localized symptoms that vary by route of infection. The case fatality rate of tularemia is typically <2% but can be higher depending on clinical manifestation and infecting strain. Tularemia is treatable with antibiotics. During 2011–2022, a total of 47 states reported 2,462 tularemia cases, but four central states (Arkansas, Kansas, Missouri, and Oklahoma) accounted for 50% of all reported cases. Incidence was highest among children aged 5–9 years (0.083 per 100,000 population) and adult males aged 65–84 years (range = 0.133–0.161). Incidence among American Indian or Alaska Native persons (0.260) was approximately five times that among White persons (0.057). The average annual incidence of tularemia in the United States during 2011–2022 (0.064) was 56% higher than that reported during 2001–2010 (0.041), largely resulting from increased reporting of probable cases. These findings might reflect an actual increase in human infection or improved case detection amid changes in commercially available laboratory tests during this period. Reducing tularemia incidence will require tailored prevention education; mitigating morbidity and mortality will require health care provider education, particularly among providers serving tribal populations, regarding early and accurate diagnosis and treatment.