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Key Points Question What were the most recent US national estimates of nurse burnout and associated factors that may put nurses at risk for burnout? Findings This secondary analysis of cross-sectional survey data from more than 3.9 million US registered nurses found that among nurses who reported leaving their current employment (9.5% of sample), 31.5% reported leaving because of burnout in 2018. The hospital setting and working more than 20 hours per week were associated with greater odds of burnout. Meaning With increasing demands placed on frontline nurses during the coronavirus disease 2019 pandemic, these findings suggest an urgent need for solutions to address burnout among nurses., This secondary analysis of a cross-sectional survey measures burnout rates and examines factors associated with leaving or considering leaving employment owing to burnout among US nurses., Importance Clinician burnout is a major risk to the health of the US. Nurses make up most of the health care workforce, and estimating nursing burnout and associated factors is vital for addressing the causes of burnout. Objective To measure rates of nurse burnout and examine factors associated with leaving or considering leaving employment owing to burnout. Design, Setting, and Participants This secondary analysis used cross-sectional survey data collected from April 30 to October 12, 2018, in the National Sample Survey of Registered Nurses in the US. All nurses who responded were included (N = 3 957 661). Data were analyzed from June 5 to October 1, 2020. Exposures Age, sex, race and ethnicity categorized by self-reported survey question, household income, and geographic region. Data were stratified by workplace setting, hours worked, and dominant function (direct patient care, other function, no dominant function) at work. Main Outcomes and Measures The primary outcomes were the likelihood of leaving employment in the last year owing to burnout or considering leaving employment owing to burnout. Results The 3 957 661 responding nurses were predominantly female (90.4%) and White (80.7%); the mean (weighted SD) age was 48.7 (0.04) years. Among nurses who reported leaving their job in 2017 (n = 418 769), 31.5% reported burnout as a reason, with lower proportions of nurses reporting burnout in the West (16.6%) and higher proportions in the Southeast (30.0%). Compared with working less than 20 h/wk, nurses who worked more than 40 h/wk had a higher likelihood identifying burnout as a reason they left their job (odds ratio, 3.28; 95% CI, 1.61-6.67). Respondents who reported leaving or considering leaving their job owing to burnout reported a stressful work environment (68.6% and 59.5%, respectively) and inadequate staffing (63.0% and 60.9%, respectively). Conclusions and Relevance These findings suggest that burnout is a significant problem among US nurses who leave their job or consider leaving their job. Health systems should focus on implementing known strategies to alleviate burnout, including adequate nurse staffing and limiting the number of hours worked per shift.