This longitudinal study among Registered Nurses has four purposes: (1) to investigate whether emotional, quantitative and physical demands, and family-work conflict have a negative impact on nurses’ perceived effort; (2) to investigate whether quality of leadership, developmental opportunities, and social support from supervisors and colleagues have a positive impact on meaning of work; (3) to investigate whether burnout from the combined impact of perceived effort and meaning of work mediates the relationship with occupational turnover intention; and (4) whether the relationships in our overall hypothesized framework are moderated by age (nurses categorized under 40 years versus ≥ 40 years old). In line with our expectations, emotional, quantitative, and physical demands, plus family-work conflict appeared to increase levels of perceived effort. Quality of leadership, developmental opportunities, and social support from supervisors and colleagues increased the meaning of work levels. In addition, increased perceived stress resulted in higher burnout levels, while increased meaning of work resulted in decreased burnout levels. Finally, higher burnout levels appeared to lead to a higher occupational turnover intention. Obviously, a nursing workforce that is in good physical and psychological condition is only conceivable when health care managers protect the employability of their nursing staff, and when there is a dual responsibility for a sustainable workforce. Additionally, thorough attention for the character of job demands and job resources according to nurses’ age category is necessary in creating meaningful management interventions.