The purpose of the present study was to investigate the moderating effect of perceived social support from friends in the associations between self-isolation practices during the COVID-19 pandemic and adolescents' mental health (i.e., depression, subjective health complaints, self-harm), measured six months later (Time 2). Participants were 1,567 7th and 8th graders (51% female; 51% white; M age = 13.67) from the United States. They completed questionnaires on perceived social support from friends, depression, subjective health complaints, and self-harm at Time 1, and self-isolation practices during COVID-19, depression, subjective health complaints, and self-harm at Time 2. The findings revealed that self-isolation practices during COVID-19 was related positively to Time 1 perceived social support from friends, and negatively to Time 2 depression, subjective health complaints, and self-harm, while accounting for Time 1 mental health outcomes. Higher perceived social support from friends at Time 1 buffered against the negative impacts on adolescents' mental health outcomes at Time 2 when they practiced greater self-isolation during COVID-19, while lower perceived social support at Time 1 had the opposite effects on Time 2 mental health outcomes.