Background: Italy was one of the first European countries to be affected by COVID-19. Due to the severity of the pandemic, the Italian government imposed a nationwide lockdown which had a great impact on the population, especially adolescents. Distance-learning, moving restrictions and pandemic-related concerns, resulted in a particularly stressful situation. Objective: This cross-sectional study aims to analyse substance consumption and its associated factors during the COVID-19 lockdown imposed by the Italian government. Methods: ESPAD is a questionnaire that is administered yearly in Italian high schools. In 2020, it was administered online during dedicated hours of distance learning, collecting data from 6027 Italian students (52.4% were male) aged 15-19. Data collected from the 2020 questionnaire was matched with that collected in 2019, in order to make them comparable. Results: The prevalence of consumption of each substance decreased during the restriction period, and the most used substance during the lockdown period was alcohol (43.1%). There were some changes in factors associated with psychoactive substance use, especially painkillers and non-prescription drugs. For instance, unlike what was observed in the 2019 model, in 2020 spending money without parental control was associated with painkillers and non-prescription drug use while risk perception was not. Conclusions: The restrictions and the increased difficulties in obtaining psychoactive substances did not prevent their consumption, and students with particular risk factors continued to use them, possibly changing the substance type of substance. This information is useful in order to better understand adolescents' substance use during the ongoing pandemic.