Background: Reactions to the COVID-19 pandemic are diverse. People who experience the situation as stressful (COVID-19 stress) appear vulnerable to developing general mental distress. Moreover, existential crises can arise. The identification of buffering factors and their effect over time is therefore highly relevant. The current study examined longitudinal protective effects of meaningfulness and self-control and negative effects of crisis of meaning on general mental distress. Methods: N=431 participants from Germany and Austria (mean age: 42 years) completed an online survey in both April/May (T1) and July/August 2020 (T2). We examined (i) whether two personal resources, meaningfulness, and self-control, measured at T1, moderated the longitudinal effect of COVID-19 stress (T1) on general mental distress (T2), and (ii) whether crisis of meaning (T1) mediated the latter effect. Results: Meaningfulness and self-control predicted lower symptoms of anxiety and depression over time, and crisis of meaning predicted higher symptoms. Meaningfulness but not self-control buffered the longitudinal effect of COVID-19 stress on general mental distress. COVID-19 stress was associated with crisis of meaning which, in further consequence, predicted general mental distress three months later. Conclusions: Meaningfulness and self-control appear to have generally protective effects on psychological distress. Moreover, meaningfulness seems to be particularly protective when people feel burdened by the situation. Strengthening this resource is thus especially appropriate for vulnerable populations. Measures that support meaningfulness will also prevent the emergence of crises of meaning, which can be triggered by acute stress reactions and appear to affect mental health in the longer term.