<p>The COVID-19 pandemic has strongly interfered with young people’s health-related quality of life (HRQoL), increasing the vulnerability of this population. As a result, researchers have been emphasizing the necessity to ascertain the protective factors against the pandemic impact. Still, little is known about these factors in adolescence. Pre-pandemic studies showed that dispositional mindfulness and emotion regulation could protect mental health and well-being. Thus, this cross-sectional study explored the relationships between dispositional mindfulness, emotion regulation, psychological distress, and HRQoL during COVID-19. The measures used to evaluate these variables were administered to 1,343 Portuguese-speaking students from Grade 5 to 12. Structural equation modelling analyses showed that adolescents’ dispositional mindfulness was related to higher HRQoL directly and indirectly through a greater employment of cognitive reappraisal and fewer employment of expressive suppression, which, in turn, was associated with fewer symptoms of anxiety and depression. These findings emphasize the importance of promoting adolescents’ dispositional mindfulness and emotion regulation to foster their mental health and, in turn, their HRQoL in difficult times.</p>