This study aimed to examine the prospective association between tobacco, alcohol and cannabis use with attaining employment among unemployed job seekers. Data from the French population-based CONSTANCES cohort on 5114 unemployed job seeking adults enrolled from 2012 to 2018 were analyzed. Binary logistic regressions were computed. Odds ratio (OR) and 95%CI of remaining unemployed at one-year of follow-up (versus attaining employment) according to substance use at baseline were obtained. The following independent variables were introduced into separate models: tobacco use (non-smoker, former smoker, light (<10cig/day), moderate (10-19cig/day) and heavy smoker (>19cig/day)), alcohol use according to the Alcohol Use Disorder Identification Test (non-users (0), low (<7), moderate (7-15) and high or very high-risk (>15)) and cannabis use (never used, no use in the previous 12 months, less than once a month, at least once a month but less than once per week, once per week or more). Analyses were adjusted for age, gender and education. At follow-up, 2490 participants (49.7%) were still unemployed. Compared to non-smokers, moderate and heavy smokers were more likely to remain unemployed, with ORs (95%CI) of 1.33 (1.08-1.64) and 1.42 (1.04-1.93), respectively. Compared to low-risk alcohol users, no alcohol users and high or very high-risk alcohol users were more likely to remain unemployed, with ORs (95% CI) of 1.40 (1.03-1.83) and 2.10 (1.53-2.87), respectively. Compared to participants who never used cannabis, participants who use cannabis once a week or more were more likely to remain unemployed, OR (95%CI) of 1.63 (1.33-2.01). Substance use may play an important role in difficulty attaining employment.