Societal trends and COVID-19 quarantines have increased the number of adolescents experiencing social isolation, placing them at heightened risk for mental health issues. The aim of this review is to explore protective factors that might mitigate psychological harm in the presence of social isolation. A systematic literature review was conducted using Fink's step-by-step process. Four library databases were searched, and results were reported using PRISMA. Of the 246 studies reviewed, 12 studies were retained following the quality assessment. The sample includes 14,064 participants from USA, Australia, and Europe, ranging from 10-19 years old. Social connectedness (ie., family connectedness, school connectedness, social support), self-esteem, and prosocial behaviors were the most common protective factors to social isolation. Additional factors such as self-efficacy, optimism, and ethnic identity are discussed. Implications for future research are recommended, including the need to explore spiritual, biological, and sociocultural factors influencing social connectedness and mental health in adolescents.