Variables associated with lifestyle can constitute either risk or protective factors for the development and progression of chronic conditions (CC). This study intends to explore the differences between adolescents with and without CC and between adolescents whose school participation is affected/not affected by the existing CC with regard to variables related to lifestyle (i.e., sleep, physical activity, BMI, and leisure). In addition, it also intends to analyze the influence of these variables (i.e., CC and lifestyle) regarding the adolescents’ quality of life (QoL). This work is part of the Portuguese HBSC 2018 study. A total of 8215 adolescents participated (52.7% female), with an average age of 14.36 years (SD = 2.28). The results showed that the adolescents with CC and whose school attendance and participation are affected by their CC exhibit more sleep difficulties (i.e., they experience lower sleep quality and have a higher degree of sleepiness), higher BMI levels (i.e., higher values of overweight and obesity), less participation in leisure activities, and a lower perception of QoL. A higher perception of QoL is associated with school participation unaffected by the existing CC, sleeping well, a low level of sleepiness, a more frequent practice of physical activity, a lower BMI, and a greater involvement in leisure activities. Adolescent health and well-being are a prominent issue in terms of public policies, with behavior and lifestyle playing a significant role in this domain. This message needs to be reinforced in regard to families, educators, healthcare professionals, and public sector policies, particularly concerning students with CC.