Understanding geographic and community-level factors associated with suicide can inform targeted suicide prevention efforts. To estimate suicide rates and trajectories, assess associated county-level contextual factors, and explore variation across the rural-urban continuum. This cross-sectional study included all individuals aged 25 to 64 years who died by suicide from January 1, 1999, to December 31, 2016, in the United States. Spatial analysis was used to map excess risk of suicide, and longitudinal random-effects models using negative binomial regression tested associations of contextual variables with suicide rates as well as interactions among county-level contextual variables. Data analyses were conducted between January 2019 and July 2019. County of residence. Three-year county suicide rates during an 18-year period stratified by rural-urban location. Between 1999 and 2016, 453 577 individuals aged 25 to 64 years died by suicide in the United States. Decedents were primarily male (349 082 [77.0%]) with 101 312 (22.3%) aged 25 to 34 years, 120 157 (26.5%) aged 35 to 44 years, 136 377 (30.1%) aged 45 to 54 years, and 95 771 (21.1%) aged 55 to 64 years. Suicide rates were higher and increased more rapidly in rural than in large metropolitan counties. The highest deprivation quartile was associated with higher suicide rates compared with the lowest deprivation quartile, especially in rural areas, although this association declined during the period studied (rural, 1999-2001: incidence rate ratio [IRR], 1.438; 95% CI, 1.319-1.568; P < .001; large metropolitan, 1999-2001: 1.208; 95% CI, 1.149-1.270; P < .001; rural, 2014-2016: IRR, 1.121; 95% CI, 1.032-1.219; P = .01; large metropolitan, 2014-2016: IRR, 0.942; 95% CI, 0.887-1.001; P = .06). The presence of more gun shops was associated with an increase in county-level suicide rates in all county types except the most rural (rural: IRR, 1.001; 95% CI, 0.999-1.004; P = .40; micropolitan: IRR, 1.005; 95% CI, 1.002-1.007; P < .001; small metropolitan: IRR, 1.010; 95% CI, 1.006-1.014; P < .001; large metropolitan: IRR, 1.012; 95% CI, 1.006-1.018; P < .001). High social capital was associated with lower suicide rates than low social capital (IRR, 0.917; 95% CI, 0.891-0.943; P < .001). High social fragmentation, an increasing percentage of the population without health insurance, and an increasing percentage of veterans in a county were associated with higher suicide rates (high social fragmentation: IRR, 1.077; 95% CI, 1.050-1.103; P < .001; percentage of population without health insurance: IRR, 1.005; 95% CI, 1.004-1.006; P < .001; percentage of veterans: IRR, 1.025; 95% CI, 1.021-1.028; P < .001). This study found that suicide rates have increased across the nation and most rapidly in rural counties, which may be more sensitive to the impact of social deprivation than more metropolitan counties. Improving social connectedness, civic opportunities, and health insurance coverage as well as limiting access to lethal means have the potential to reduce suicide rates across the rural-urban continuum.