Abstract Objectives The main purpose of this longitudinal study was to elucidate the impact of external job mobility, due to a change of employer, on mental health. Methods A cohort of Belgian employees from the IDEWE occupational medicine registry was followed-up for twenty-seven years, from 1993 to 2019. The use of drugs for neuropsychological diseases was considered as an objective indicator of mental health. The covariates were related to demographic, physical, behavioural characteristics, occupational and work-related risks. Propensity scores were calculated with a Cox regression model with time-varying covariates. The PS matching was used to eliminate the systematic differences in subjects’ characteristics and to balance the covariates’ distribution at every time point. Results The unmatched sample included 11,246 subjects, with 368 (3.3%) that changed their job during the baseline year and 922 (8.2%) workers that left their employer during the follow-up. More than half of the matched sample were males, were aged less than 38 years old, did not smoke, were physically active, and normal weighted, were not exposed to shift-work, noise, job strain or physical load. A strong association between job mobility and neuropsychological treatment was found in the matched analysis (HR = 2.065, 95%CI = 1.397–3.052, P-value < 0.001) and confirmed in the sensitivity analysis (HR of 2.012, 95%CI = 1.359–2.979, P-value < 0.001). Furthermore, it was found a protective role of physical activity and a harmful role of job strain on neuropsychological treatment. Conclusions Our study found that workers with external job mobility have a doubled risk of treatment with neuropsychological medication, compared to workers without job mobility.