This study examines the long-term dynamics of social stressors at work, psychological detachment, and their impact on employee well-being. Previous research has shown that social stressors are detrimental for employee well-being and the ability to mentally detach from work. However, longitudinal studies in this field are scarce, and typically, they only explore whether the level of stressors, or of detachment, at a given point in time has an effect on outcomes. That stressors and detachment may change over time, and that this change may have an independent effect in the process, has rarely been taken into consideration. Thus, it is unclear to what extent long-term dynamic effects also play a role in these relations. To address this question, we investigated whether change in detachment explains the long-term indirect relationship of change in perceived social stressors with change in emotional exhaustion and mental well-being. Data were taken from a longitudinal study of N = 246 registered nurses with up to 3 measurements over 1 year. Analyses were conducted with latent difference scores using a proportional change model. Results revealed that a decline in psychological detachment mediated the long-term effects of increases in social stressors at the workplace on subsequent change in emotional exhaustion and mental well-being. Thus, our study provides initial evidence for the underlying long-term dynamic nature of relationships among social stressors, detachment, and employee well-being, highlighting the incremental explanatory power of change in social stressors and in detachment, above and beyond their respective levels, in predicting change in well-being.