COVID-19-related national lockdowns worldwide have had repercussions on people’s well-being and have led to increased substance use. Mindfulness has previously been associated with reduced psychological distress and benefits in terms of addictive behaviors. We aimed to assess whether dispositional mindfulness protected against increased tobacco and alcohol use in hospital workers after France’s first lockdown started. All workers in two French hospitals were contacted by email to participate in an online survey. Three hundred eighty-five workers answered. We ran two separate logistic regression models to test for associations between the level of dispositional mindfulness and both increased tobacco and alcohol use, after adjusting for affect deterioration. Dispositional mindfulness was associated with a lower likelihood of increased tobacco (adjusted odds ratio (AOR) [95% CI] 0.71 [0.51; 0.99], p = 0.046) and alcohol (0.66 [0.50; 0.87], p = 0.004) use. The effect of mindfulness on tobacco use was partially mediated by affect deterioration. Dispositional mindfulness appeared to be a protective factor against lockdown-related tobacco and alcohol use increases in French hospital workers.