Introduction: Black, Indigenous, and people of color (BIPOC), and Lesbian, Gay, Bisexual, and Trans—sometimes referred to as Queer and Trans (QT)—minoritized youth face elevated risks of depression linked to intersectional discrimination and internalized stigma. Caregiver messaging of acceptance or rejection has the potential to worsen or mitigate these relationships. This study examines how discrimination relates to depression, whether internalized stigma mediates this link, and if caregiver messaging moderates these effects. Methods: Using the 2022 LGBTQ National Teen Survey, data on 1,229 intersectional QT-BIPOC youth (mean age of 15) were analyzed using two moderated mediation models. Results: No significant moderated mediation effects emerged. However, internalized stigma consistently mediated the link between discrimination and depression. Discussion: While neither moderated mediation model was significant, internalized stigma and caregiver messages may still play important roles in well-being. Future research should explore intersectional socialization and its impact on well-being for QT-BIPOC youth.