This study investigates the relationships among social isolation, psychological health, and protective factors in adolescents. Feelings of social isolation may influence psychological health in adolescents, but protective factors such as family connectedness, school connectedness, and academic achievement may also play a key role. The sample included 4,746 adolescents from 31 middle and high schools. Participants responded to 221 survey questions regarding peer relationships, psychological health, school connectedness, family relationships, and academic achievement. The findings revealed that social isolation was associated with an increased risk for depressive symptoms, suicide attempts, and low self-esteem. Protective factors influenced associations between social isolation and psychological health. Implications for prevention such as building healthy peer relationships, promoting family connectedness, and developing school-based interventions are discussed.