The COVID-19 pandemic is a unique period of stress and uncertainty that will have significant implications for adolescent mental health. Nevertheless, stress about COVID-19 may be more consequential for some adolescents’ mental health than for others. We examined whether heart rate variability (HRV) indicated differential susceptibility to mental health difficulties associated with COVID-19 stress. Approximately four years prior to the pandemic, we assessed resting HRV and HRV reactivity to a well-validated stress paradigm in 87 adolescents. During the pandemic, these adolescents (ages 13-19) reported on their health-related stress and concerns about COVID-19 and their recent emotional problems. The association between COVID-19 stress and emotional problems was significantly stronger for adolescents who previously exhibited higher resting HRV or higher HRV reactivity. For adolescents who exhibited lower resting HRV or lower HRV reactivity, COVID-19 stress was not associated with emotional problems. Thus, parasympathetic functioning may reflect differential susceptibility to the effects of COVID-19 stress on mental health during the pandemic.