Regular or problematic use of psychoactive substances is more common among job seekers than among employed individuals. In order to identify the populations that should be prioritized for intervention and the possible levers for action, it is necessary to understand the factors associated with such use. This study consisted of a secondary analysis of data from the 2010 Health Barometer, a national survey conducted among a large representative sample of the French population regarding the use of tobacco, alcohol, and cannabis. Unemployed individuals with less than a high school diploma and, among men, manual laborers, were the most likely to smoke tobacco. Among job seekers, risky alcohol consumption appeared particularly high among the youngest and among men aged 45–54. While, for men, risky alcohol use was more common among those without a high school diploma, for women, it was managers and professionals who engaged in the most health-risking behaviors. Regular cannabis use, which primarily affected younger individuals, was associated with a low level of education and the blue-collar worker category among unemployed men. Unemployed individuals who had experienced violence and those suffering from psychological distress exhibited more pronounced addictive behaviors, though it was not possible to distinguish between contextual effects and causal relationships. Regardless of the nature of the link between unemployment and psychoactive substance use, the population of job seekers must be the target of a targeted preventive program.