Background: The stimulation-seeking theory posits that individuals with low habitual autonomic arousal levels will seek stimulation to increase their arousal to more optimal levels. Because of their assumed high optimal stimulation levels, persons characterized by low autonomic arousal may be better able to endure stressors than those with higher levels. In this study, we tested the hypothesis that low resting heart rate (HR) and high respiratory sinus arrhythmia (RSA) protect against the detrimental effects of stressors on mental health in early adolescents from the general population. Methods: Data were collected as part of TRacking Adolescents' Individual Lives Survey (TRAILS), a large prospective cohort of Dutch (pre)adolescents (N = 1478), with measurements at approximately age 11(T1) and age 13.5 (T2). Internalizing and externalizing mental health problems were assessed at both waves, using multiple informants. Resting HR ands RSA were assessed at T1 and the amount of parent-reported stressors and long-term difficulties at T2. Results: Stressors predicted mental health problems in adolescents with intermediate and high HR, but not in those with low HR. These findings were consistent regardless of the measure used to assess stressors and of adjustment for T1 mental health problems. Furthermore, the stress-buffering effects of low HR pertained to both externalizing problems and internalizing problems. No stress-buffering effects were found for RSA, suggesting predominantly sympathetic influences. Conclusions: Our study, which linked physiologic measures to stress sensitivity in real life, suggests that low HR is a marker of resilience to the effects of environmental challenges in early adolescence.