The aim of this study was to investigate the occupational well-being among employees with chronic diseases, and the buffering effect of four job resources, possibly offering targets to enhance occupational well-being. Method: This cross-sectional study (N = 1951) was carried out among employees in educational and (semi-)governmental organizations in the Netherlands. The dimensions of the survey were chronic diseases (i.e., physical, mental, or both physical and mental), occupational well-being (i.e., work ability, burnout complaints, and work engagement), and job resources (i.e., autonomy, social support by colleagues, supportive leadership style, and open and communicative culture). First, it was analyzed if chronic diseases were associated with occupational well-being. Second, it was analyzed if each of the four job resources would predict better occupational well-being. Third, possible moderation effects between the chronic disease groups and each job resource on occupational well-being were examined. Regression analyses were used, controlling for age. Results: Each chronic disease group was associated with a lower work ability. However, higher burnout complaints and a lower work engagement were only predicted by the group with mental chronic diseases and by the group with both physical and mental chronic disease(s). Furthermore, all four job resources predicted lower burnout complaints and higher work engagement, while higher work ability was only predicted by autonomy and a supportive leadership style. Some moderation effects were observed. Autonomy buffered the negative relationship between the chronic disease groups with mental conditions (with or without physical conditions) and work ability, and the positive relationship between the group with both physical and mental chronic disease(s) and burnout complaints. Furthermore, a supportive leadership style is of less benefit for occupational well-being among the employees with mental chronic diseases (with or without physical chronic diseases) compared to the group employees without chronic diseases. No buffering was demonstrated for social support of colleagues and an open and communicative organizational culture.