Social outsiderhood among adolescents including loneliness and ostracism is a threat to public health affecting their psychological well-being and increasing the risk for externalizing problems, such as substance use. Nevertheless, less is known about teacher and family support as possible protective factors between social outsiderhood and psychological well-being and substance use among adolescents. This study examined a.) the role of loneliness (social and emotional) and perceived ostracism in adolescents’ psychological well-being (positive mental health and psychological symptoms) and substance use, and b.) perceived teacher and family support and grade level as moderators between these associations. A total of 2241 Finnish adolescents (Grade 7: 1218, M age 13.90 years, 50% girls; Grade 9: 1023, M age 15.91 years, 52.5% girls) completed a cross-sectional self-report survey in 2022. The results showed that higher levels of social loneliness and perceived ostracism were associated with poorer psychological well-being, whereas higher levels of emotional loneliness were more strongly associated with frequent substance use. While high teacher support buffered against lower mental health in adolescents with high perceived ostracism, high family support buffered against lower mental health in those with high social loneliness. Higher levels of emotional loneliness were more strongly linked to frequent substance use and lower mental health in older students, whereas the negative association between social loneliness and mental health was stronger in younger students. These results suggest that it is important to identify the form of social outsiderhood adolescents experience when developing interventions for the affected adolescents. More knowledge and tools should be provided to teachers during teacher education to help identify ostracized students.