Background: The aim of this study was to evaluate the trends of prevalence of health risk behaviors (HRBs) and health conditions over a 10 year period (2008–2018) in a representative sample of adolescents of Tuscany Region, Italy. Methods: This was a repeated cross-sectional (four survey waves) study. The prevalence of 17 HRBs and health conditions were analyzed by age, sex, and socioeconomic status (SES). Results: A total of 21,943 students were surveyed. During the study period, decreases in smoking participation, cocaine use, driving under the influence of alcohol and drugs, and problem gambling were observed, while alcohol abuse and at-risk sexual behaviors remained unchanged or increased. Males resulted more frequently involved in most of the HRBs, while females more frequently reported physical inactivity, regular smoking, and not using a condom. Female participation in smoking and alcohol abuse behaviors, fruit and vegetable consumption, and bullying worsened over the study period. Smoking, poor dietary habits, physical inactivity, high distress level, and obesity were more frequently observed in low-SES students than in high-SES students. Conclusions: The findings showed different tendencies in adolescent participation in HRBs over the last decade; concerning trends in at-risk sexual behaviors and alcohol consumption and females’ risk-taking behavior on the rise require careful monitoring.