A negative school climate resulting from homophobic and transphobic bias and discrimination is associated with poor well-being and mental health among LGBTQ+ youth. However, protective factors and mechanisms may buffer against the impact of stigmatization. Drawing on the socio-ecological model, minority stress theory, and positive youth development and agency perspectives, we carried out a systematic review of research focusing on factors that can promote the well-being of LGBTQ+ students in educational settings, outlining the primary outcomes from studies published between 2012 and 2022. The PRISMA protocol was used for this review, and 64 articles were scrutinized. The results of the thematic analysis revealed that both external factors (school-inclusive policies and extracurricular activities; social support from school, family, and the community; and school connectedness) and internal factors (psychosocial characteristics and personal agency) promote positive school experiences, such as the exploration of sexual and gender identities in a safe environment. The present findings highlight the need for inclusive school policies and strategies and individual-level interventions that target the well-being and positive mental health outcomes of sexual and gender minority students.