Introduction: Healthcare systems have not yet adequately responded to the burden of mental disorders, especially among children and adolescents who experience mental disorders worldwide. If untreated, these conditions severely influence children’s development, educational attainments, and potential to accomplish their lives. Antonovsky proposed salutogenesis contributing with a theoretical and empirical basis through the concept of Sense of Coherence (SOC) to improve mental health. The general objective of this research is to analyze the sense of coherence and self-esteem among children and adolescents with respect to their academic achievement. Methods: A mixed method including a cross-sectional design and qualitative interviews was used. Part of the sample (N=199) was recruited from elementary, vocational, and high schools in Szeged, and the other part (N=124) was from patients of the Child and Adolescent Psychiatry Unit of the University of Szeged, Hungary. Mean age of the sample was 14.3 (SD 2.1) years. The instruments used were the Sense of Coherence Scale (SOCS), Rosenberg Self-Esteem Scale (RSE), Strengths and Difficulties Questionnaire (SDQ), Quality of Life Scale (ILK), Multidimensional Scale of Perceived Social Support (MSPSS), demographic and negative life events questionnaire. Results: Confirmatory factor analysis showed the 3-factor model superior to the unidimensional one on both samples. SOCS-13 significantly differentiated between average children/adolescents and youth under psychiatric care. Self-esteem, quality of life, and subjective social support were significantly lower in the psychiatric sample. Children had higher SOC, higher self-esteem, and better quality of life than adolescents in both the average and psychiatric subsamples. Self-esteem, quality of life, social support, and psychiatric symptoms significantly predicted SOC. School grade was associated with SOC, age, gender, and psychological and behavioral symptoms. SOC was a significant predictor of grade only in the average sample. Emotional symptoms seemed to be the strongest predictors of academic achievement among all psychological/behavioral symptoms in the psychiatric sample. The qualitative study showed that participants with depressive symptoms didn’t understand themselves, managed themselves badly, and either didn’t know their meaning or found themselves meaningless revealing low SOC, low self-esteem, and a lack of purpose in their lives. Conclusion: Quality of life must become an important goal of psychiatric programs of treatment, especially when psychopathology tends to remain. The assessment of sense of coherence and psychological/behavioral symptoms considering the age and gender of the youth should be a priority to prevent deterioration in grades and give support for the adaptation of changes occurring during these stages of life.