Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes or ticks, and in the continental United States, West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease. Other arboviruses cause sporadic cases of disease as well as occasional outbreaks. This report summarizes 2021 surveillance data reported to CDC by U.S. jurisdictions for nationally notifiable arboviruses; the report excludes chikungunya, dengue, yellow fever, and Zika virus disease cases, because these infections were acquired primarily through travel during 2021. Forty-nine states and the District of Columbia reported 3,035 cases of domestic arboviral disease, including those caused by West Nile (2,911), La Crosse (40), Jamestown Canyon (32), Powassan (24), St. Louis encephalitis (17), unspecified California serogroup (six), and eastern equine encephalitis (five) viruses. Among the WNV disease cases, 2,008 (69%) were classified as neuroinvasive disease, for a national incidence of 0.61 cases per 100,000 population. Because arboviral diseases continue to cause serious illness, maintaining surveillance programs to monitor their transmission and prevalence is important to the direction and promotion of prevention activities. Health care providers should consider arboviral infections in the differential diagnosis of aseptic meningitis and encephalitis, obtain appropriate specimens for laboratory testing, and promptly report cases to public health authorities. Prevention depends on community and household efforts to reduce vector populations and personal protective measures to prevent mosquito and tick bites, such as use of Environmental Protection Agency-registered insect repellent and wearing protective clothing.