Adolescence is an unpredictable stage of life with varied and rapid changes. In Jordan, health-related quality of life (HRQoL) has been examined among diabetic and obese children and adolescents. The purpose of this study was to assess the HRQoL of Jordanian healthy adolescents. Three hundred fifty-four male and female adolescents whose ages ranged from 12 to 19 participated in the study. A descriptive comparative design was employed to investigate adolescents’ HRQoL. The results revealed statistically significant differences in physical well-being, psychosocial well-being, and autonomy in favor of male adolescents. In addition, statistically significant differences were observed in favor of nonsmoker adolescents in psychosocial well-being, self-perception, parent relations and home life, financial resources, social relations and peers and school environment. In conclusion, the creation of a school health nurse role in Jordanian schools is crucial for helping adolescents improve their health.