Objectives. To examine nurses' well-being and identify individual and workplace factors associated with adverse outcomes. Methods. We administered an e-mail survey to registered nurses in Michigan in March 2022. Outcomes included the Oldenburg Burnout Inventory-Exhaustion scale, self-harm thoughts (yes/no), and overall wellness on a 0 to 10 visual analog scale. Covariates included practice environment, psychological safety, workplace abuse, staffing adequacy, stress coping strategies, and demographics. We examined associations between covariates and exhaustion, thoughts of self-harm (both via logistic regression), and overall wellness (via linear regression). Results. Among surveyed nurses, 93.63% reported significant exhaustion, 9.88% reported self-harm thoughts, and the mean (SD) overall wellness score was 6.2 (2.3). Factors associated with exhaustion included inadequate staffing, lower psychological safety, and younger age. Factors associated with self-harm thoughts included recent workplace physical abuse and younger age. Factors associated with higher wellness scores included employer support, favorable practice environments, higher job satisfaction, and positive coping strategies. Conclusions. Negative well-being outcomes were prevalent among registered nurses and were associated with correctable workplace deficits. Nurses' well-being is a national public health problem that warrants comprehensive interventions at individual, workplace, and community levels. (Am J Public Health. 2024;114(S2):S180-S188. https://doi.org/10.2105/AJPH.2023.307376).