Background: Adolescents’ quality of life is reported to be significantly associated with physical and social wellbeing. Although adolescents are 30% of the Southern African population, no previous studies have focused on this group in relation to oral health and quality of life. Methods: A 40-item survey and clinical oral examinations were conducted in public schools in Maseru from 10 to 25 August 2016. Simple, bivariate, and multivariate regressions were used to evaluate the associations of oral health and psychosocial factors with self-reported general health status and quality of life. Results: A total of 526 participants, aged 12–19 years old, responded to the survey and participated in the clinical examinations. The majority reported a good (good/very good/excellent) quality of life (84%) and general health (81%). Bivariate results showed that self-reported general health in this population was significantly influenced by age. The presence of toothache and sensitivity in the adolescents were significantly associated with poor (fair/poor) self-reported general health and were found to be the best predictors for self-general health and quality of life. Conclusions: The absence of dental conditions such as toothache and tooth sensitivity can lead to a better perception of general health and Quality of Life in adolescents.