As time passes, the long-term effects of the COVID-19 pandemic are becoming increasingly apparent. The extreme restrictions imposed during the pandemic have had detrimental impacts on the most vulnerable groups, such as individuals suffering from substance and/or alcohol disorders (SUDs). This study reports quarterly laboratory data on alcohol and drug use in 150 subjects with SUDs that were examined using hair analysis for 2 years before the start of pandemic until after the end of the Italian health emergency. Overall, it was found that the number of subjects who used heroin, cocaine, and MDMA all decreased during the 2020 and 2021 lockdowns, increasing during reopening and subsequently stabilizing close to pre-COVID levels. Cannabis use was less impacted, remaining stable throughout the pandemic. Alcohol and benzodiazepine use both increased significantly during the lockdowns, displaying an opposing trend. While benzodiazepine use progressively returned to baseline levels, alcohol remained at significantly increased levels, even in September 2022. Long-term heavy drinking combined with substance use should be seriously considered, since these results in several health and social problems alongside alcohol-related comorbidities. Thus, appropriate response plans should be implemented both during and after the pandemic, whilst focusing on those who are most vulnerable.