Mental health self-management (MHS) strategies may help workers with mental health concerns preserve and enhance their well-being. However, little research has explored how these strategies may help mitigate the effects of negative psychosocial work factors (PWFs) on well-being outcomes. This cross-sectional study investigated (1) the relationship between PWFs and well-being, (2) the association between MHS at work and well-being, and (3) the moderating role of self-management in preventing negative PWFs' deleterious effects. A sample of 896 Francophone workers in Canada completed a questionnaire that included self-reported measures related to workplace, self-management, and well-being. Structural equation modeling (conducted via the MPlus software, version 8.6) revealed that psychological demands were negatively related to positive well-being outcomes and positively associated with adverse well-being outcomes. Competency-related autonomy was positively associated with flourishing, and recognition was positively associated with flourishing and positive well-being at work, as well as being negatively associated with burnout and depression. Surprisingly, supervisor support was negatively related to positive well-being and positively related to burnout and depression. MHS was positively associated with positive well-being at work, flourishing, and work performance, but had no relationship with negative mental health. MHS significantly moderated the relationship between each PWF and well-being at work in both beneficial and adverse ways, depending on the specific well-being indicator being considered. From a workplace well-being perspective, this suggests that although self-management may help workers preserve and enhance their positive well-being, organizations must also directly target PWFs to prevent negative well-being outcomes.