Purpose: Exhaustion symptoms are known to be associated with cardiovascular disease (CVD) risk; however, the underlying mechanisms remain unclear. Autonomic imbalance, as indicated by reductions in vagally-mediated heart rate variability (vmHRV), appears to be a valid candidate for such a biological link, as it has been associated with both exhaustion symptoms and CVD risk and mortality. Methods: The present study examined a potential mediation of vmHRV on the association between exhaustion symptoms and self-reported CVD risk factors as well as the age dependency of this mediation in a large, heterogeneous sample of the Dresden Burnout Study (N = 388; 72.9% females; M_age = 42.61, SD = 11.67). Results: Results indicate that exhaustion symptoms were indirectly associated with CVD risk factors through vmHRV even after adjusting for well-known confounders (i.e., sex, body mass index, depressive symptoms). Moreover, this pattern was significant only among middle-aged (i.e., 54.27 years) and older individuals. Conclusions: Our findings add to growing evidence that autonomic imbalance may be a key biological link between exhaustion symptoms and CVD risk in middle-aged and older individuals. Implications for public health are discussed.