Background: At times, the question for meaning comes to nothing and a crisis of meaning ensues. This state is very painful, but difficult to account. Both those who suffer from it and care professionals find themselves at a loss for words. Aims: This study introduces an operationalization of a crisis of meaning. It aims to distinguish the concept from depression, and to investigate whether a crisis of meaning can explain suicidality beyond the known protective and risk factors self-esteem, family functioning, life-event load, and depression. Method: Final-year school pupils in Ecuador (N = 300) completed questionnaires assessing the above variables. Data were analyzed using chi-square, hierarchic multiple regression, serial mediation, and moderator analyses. Results: Crisis of meaning was distinguished from depression. It explained a significant amount of variance in suicidality beyond the mentioned protective and risk factors. For males, crisis of meaning was the only significant risk factor, and the strongest predictor overall. The acute risk factors depression and crisis of meaning mediated the effects of the baseline factors self-esteem, family functioning, and life-event load on suicidality. Limitations: The study was cross-sectional; assessed factors predicted variance in suicidal thoughts, plans, and past suicide attempts, while their relevance cannot be generalized to actual future suicide attempts. Conclusion: A crisis of meaning is an important factor to take into account in further research on the prevention and treatment of people at risk of suicide.