Aims: Working conditions, especially psychosocial work factors (PWFs), are thought to influence mental health outcomes among working populations, but there have been few studies on well-being per se. We assessed the prospective associations between a wide variety of occupational factors, including PWFs, multiple exposure to these factors, and well-being among employees in France. Methods: This study was based on a nationally representative sample of 15,776 employees, including 6595 men and 9181 women, followed up from 2013 to 2016. Psychological well-being was assessed using the WHO-5 Well-Being Index. Occupational factors included 20 PWFs, 4 factors related to working time/hours, and 4 physical work exposures. The associations of occupational exposures with poor well-being were estimated using weighted robust Poisson regression models in men and women separately. Results: Among the employees who rated their well-being as good in 2013, 10.3% of men and 16.8% of women had a poor well-being 3 years later. Most PWFs in 2013 were associated with poor well-being in 2016 among women, and half of them among men. An increase in the risk of poor well-being with the number of PWFs was found. Noise exposure was associated with poor well-being in women. Conclusions: The occupational factors associated with psychological well-being were mainly those related to the psychosocial work environment. A linear association was observed between the number of exposures to PWFs and well-being. Preventive policies focused on PWFs may be beneficial for well-being. More attention should be given to multiple exposures to these factors.