The purpose of the present study was to investigate the individual and combined impact of physical fitness components at baseline on health-related quality of life (HRQoL) at 24-month follow-up in adolescents. This longitudinal research included 199 adolescents (13.9±0.3 years at baseline) from the DADOS study. Cardiorespiratory fitness was assessed using the 20-m shuttle run test. Muscular strength was assessed using the standing broad jump test. Motor competence was assessed using the 4 × 10-m shuttle run test. A physical fitness z-score was calculated as the mean of the z-scores values of each fitness test. A fitness index ranging from 0 to 3 was created according to the number of physical fitness components in which participants achieved high levels according to normative values. HRQoL was evaluated by the KIDSCREEN-10 questionnaire. Linear regression analyses showed that cardiorespiratory fitness, muscular strength, and the physical fitness z-score at baseline were individually associated with HRQoL at follow-up (β ranging from 0.123 to 0.183; all < 0.05). Moreover, logistic regression analysis revealed that adolescents with a fitness index ≥1 at baseline were more likely to achieve high HRQoL at 24-month follow-up, compared with their peers with an index of 0 (OR ranging from 3.554 to 9.087; all < 0.05). Our results revealed an individual and cumulative positive impact of physical fitness at baseline on HRQoL at 24-month follow-up These findings underline the key role of promoting the enhancement of overall physical fitness components in order to improve adolescents' health and well-being. Adolescents with high levels of cardiorespiratory fitness, muscular strength and motor competence will benefit from a greater physical and mental well-being over the time.The more physical fitness components with optimal levels, the greater likelihood of reaching better HRQoL over the time.Public health authorities should focus on the promotion of multiple physical fitness components to increase adolescent's likelihood of achieving greater HRQoL over the time.