Prospective studies exploring the associations between a large range of occupational factors and psychotropic drug use among national samples of workers are seldom. This study investigates the cross-sectional and prospective associations between occupational factors, including a large set of psychosocial work factors, and psychotropic drug use in the national French working population. The study sample comprised 7542 workers for the cross-sectional analysis and 4213 workers followed up for a 4-year period for the prospective analysis. Psychotropic drug use was measured within the last 12 months and defined by the use of antidepressants, anxiolytics or hypnotics. Three groups of occupational factors were explored: classical and emergent psychosocial work factors, working time/hours and physical work exposures. Weighted Poisson regression analyses were performed to adjust for covariates. In the cross-sectional analysis, psychological demands, low social support and hiding emotions were associated with psychotropic drug use. Job insecurity for men and night work for women were associated with psychotropic drug use. In the prospective analysis, hiding emotions and physical exposure were predictive of psychotropic drug use. Dose-response associations were observed for the frequency/intensity of exposure and repeated exposure to occupational factors. This study underlines the role of psychosocial work factors, including emergent factors, in psychotropic drug use. Prevention policies oriented toward psychosocial work factors comprehensively may be useful to reduce this use.