Objective: The study aimed at analyzing the relationship between anthropometric characteristics, lifestyle, and dietary habits, as well as the burden of the pandemic on the health-related quality of life among Greek pupils. Research methods and procedures: On the whole, 2088 adolescents aged 12–18 years from Attica, Greece, were enlisted in this school-based cross-sectional study that took place in May–December 2021. Health-related quality of life was estimated through the KIDSCREEN-27 questionnaire, adherence to the Mediterranean diet—through the KIDMED test. For the empirical and econometric analyses, the Mann–Whitney U and Kruskal–Wallis means comparison tests were utilized; multiple linear regression was used accordingly. Results: The present study provides evidence to the fact that boys, younger adolescents, adolescents living with both parents and with highly educated mothers had a better health-related quality of life. Concerning their eating practices, positive predictors were consuming a better-quality breakfast, having all five meals daily, consuming lunch and dinner with parents, and higher adherence to the Mediterranean diet. Moreover, sufficient night sleep time, fewer hours spent on screen viewing, more frequent walks, and having hobbies were linked to the health-related quality of life with a positive sign. In contrast, negative predictors were higher body mass index and everyday life difficulties due to the COVID-19 pandemic crisis. Conclusions: Greek adolescents’ anthropometric characteristics, BMI, lifestyle and sedentary habits, eating habits, and adherence to the Mediterranean diet were significantly related to their perceived health-related quality of life during the pandemic.