Patterns in emergency department (ED) use by rural populations may be an important indicator of the health care needs of individuals in the rural United States and may critically affect rural hospital finances. To describe urban and rural differences in ED use over a 12-year period by demographic characteristics, payers, and characteristics of care, including trends in ambulatory care-sensitive conditions and ED safety-net status. This cross-sectional study of ED visit data from the nationally representative National Hospital Ambulatory Medical Care Survey examined ED visit rates from January 2005 to December 2016. Visits were divided by urban and rural classification and stratified by age, sex, race/ethnicity, and payer. Emergency departments were categorized as urban or rural in accordance with the US Office of Management and Budget classification. Codes from the International Classification of Diseases, Ninth Revision (ICD-9), were used to extract visits related to ambulatory care-sensitive conditions. Safety-net status was determined by the Centers for Disease Control and Prevention definition. Visit rates were calculated using annual US Census Bureau estimates. National Hospital Ambulatory Medical Care Survey estimates were generated using provided survey weights and served as the numerator, yielding an annual, population-adjusted rate. Data were analyzed from June 2017 to November 2018. Emergency department visit rates for 2005 and 2016 with 95% confidence intervals, accompanying rate differences (RDs) comparing the 2 years, and annual rate change (RC) with accompanying trend tests using weighted linear regression models. During the period examined, rural ED visit estimates increased from 16.7 million to 28.4 million, and urban visits increased from 98.6 million to 117.2 million. Rural ED visits increased for non-Hispanic white patients (13.5 million to 22.5 million), Medicaid beneficiaries (4.4 million to 9.7 million), those aged 18 to 64 years (9.6 million to 16.7 million), and patients without insurance (2.7 million to 3.4 million). Rural ED visit rates increased by more than 50%, from 36.5 to 64.5 visits per 100 persons (RD, 28.9; RC, 2.2; 95% CI, 1.2 to 3.3), outpacing urban ED visit rates, which increased from 40.2 to 42.8 visits per 100 persons (RD, 2.6; RC, 0.2; 95% CI, -0.1 to 0.6). By 2016, nearly one-fifth of all ED visits occurred in the rural setting. From 2005 to 2016, rural ED utilization rates increased for non-Hispanic white patients (RD, 26.1; RC, 1.6; 95% CI, 0.4 to 2.8), Medicaid beneficiaries (RD, 56.4; RC, 4.1; 95% CI, 2.1 to 6.1), those aged 18 to 44 years (46.9 to 81.6 visits per 100 persons; RD, 34.7; RC, 2.3; 95% CI, 1.1 to 3.5) as well as those aged 45 to 64 years (27.5 to 53.9 visits per 100 persons; RD, 26.5; RC, 1.6; 95% CI, 0.7 to 2.5), and patients without insurance (44.0 to 66.6 visits per 100 persons per year; RD, 22.6; RC, 2.7; 95% CI, 0.2 to 5.2), with a larger proportion of rural EDs categorized as safety-net status. Rural EDs are experiencing important changes in utilization rates, increasingly serving a larger proportion of traditionally disadvantaged groups and with greater pressure as safety-net hospitals.