: We aim to assess the effect of the Espaijove.net mental health literacy program on adolescents' quality of life (QOL). Additionally, we aim to describe their QOL and mental well-being. : A multicenter, randomized, controlled trial was conducted, with pre- and post-intervention assessments and 6- and 12-month follow-ups. A total of 1032 students aged 13-14 from 18 schools in Barcelona participated in one of the three following mental health literacy (MHL) programs or were placed in a control group (CG): (1) a 1 h awareness session (G1h); (2) a 6 h MHL program (G6h); (3) a 7 h MHL program with stigma reduction (G7h). Measures: (1) Mental well-being: Strengths and Difficulties Questionnaire (SDQ); (2) QOL: EuroQol 5D-5L with its two parts: the EuroQol 5D-5L Index (0-1) and EuroQol 5D-5L visual analog scale (EQ-VAS) (0-100). Analyses were conducted on an intention-to-treat basis, using data imputation methods for missing data. Intervention effects were assessed using multilevel models. : Baseline EQ-VAS and EQ-5D-5L index scores were 77.84 (CI = 76.77-78.91) and 0.91 (CI = 0.90-0.92), respectively. Boys reported higher QOL and SDQ scores ( < 0.001), whereas participants of foreign nationality showed lower scores in QOL (EQ-VAS; = 0.039) and mental well-being ( < 0.001). Post-intervention, all groups (intervention and control), except G6h, showed QOL improvements. However, in the 6-month follow-up, the CG outperformed the other groups. At 12 months, G7h achieved the highest EQ-VAS scores compared to the other groups. : MHL-based interventions improved short-term QOL but failed to sustain these improvements over time. Groups with lower QOL and SDQ scores included girls and adolescents of foreign nationality.