Background: The coronavirus disease 2019 pandemic has led to an increase in youth mental health problems worldwide. Studies have revealed substantial variation in the incidence of these problems across different regions. Longitudinal studies of children and adolescents in Italy are lacking. This study aimed to investigate the development of health-related quality of life (HRQoL) and mental health in Northern Italy by comparing surveys conducted in June 2021 and in March 2022. Methods: A representative, large cross-sectional, online survey investigated HRQoL, psychosomatic complaints, and symptoms of anxiety and depression among 5159 and 6675 children and adolescents in 2021 and 2022, respectively, using the KIDSCREEN-10 index, HBSC symptom checklist, SCARED, CES-DC, and PHQ-2 instruments. Statistical analyses included a multivariate linear regression analysis. Results: Baseline characteristics showed significant differences in demographic variables between the two surveys. Girls and their parents reported a significantly lower HRQoL in 2021 than in 2022. Psychosomatic complaints differed significantly between sexes, and the results showed no decrease in psychosomatic complaints, anxiety, or depression between 2021 and 2022. Predictors of HRQoL, anxiety, depressive symptoms, and psychosomatic complaints in 2022 differed from those in 2021. Conclusions: The characteristics of the 2021 pandemic, including lockdowns and home schooling, may have contributed to the differences between the two surveys. As most pandemic restrictions ended in 2022, the results confirm the need for measures to improve the mental and physical health of children and adolescents after the pandemic.