Poor physiological self-regulation has been proposed as a potential biological vulnerability for adolescent suicidality. This study tested this hypothesis by examining the effect of parasympathetic stress responses on future suicide ideation. In addition, drawing from multilevel developmental psychopathology theories, the interplay between parasympathetic regulation and friendship support, conceptualized as an external source of regulation, was examined. At baseline, 132 adolescent females (M age = 14.59, SD = 1.39) with a history of mental health concerns participated in an in vivo interpersonal stressor (a laboratory speech task) and completed self-report measures of depressive symptoms and perceived support within a close same-age female friendship. Respiratory sinus arrhythmia (RSA) was measured before and during the speech task. Suicide ideation was assessed at baseline and at 3, 6, and 9 months follow-up. The results revealed that females with greater relative RSA decreases to the laboratory stressor were at higher risk for reporting suicide ideation over the subsequent 9 months. Moreover, parasympathetic responses moderated the effect of friendship support on suicide ideation; among females with mild changes or higher relative increases in RSA, but not more pronounced RSA decreases, friendship support reduced risk for future suicide ideation. Findings highlight the crucial role of physiological and external regulation sources as protective factors for youth suicidality.