**[Link to MIDUS data][1]** **Abstract** The two branches of the autonomic nervous system (ANS) have been individually linked to age-related changes in cognitive functioning: The parasympathetic nervous system (PNS) is thought to support healthy cognitive aging, whereas the sympathetic nervous system (SNS) has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on age-related cognitive changes. We examined cognitive change in two waves of the Midlife in the United States (MIDUS) study cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels, respectively, from the MIDUS biomarker project (minimum n = 843, 57.9% female, mean age at first wave = 53.8 years). Our findings indicate that greater PNS flexibility (i.e., greater withdrawal and greater recovery) in response to cognitive challenge is associated with attenuated cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the effects of the PNS on cognitive decline are attenuated. This pattern was most robust among younger individuals in the sample, who were transitioning to midlife. These results suggest that interventions targeting the ANS as a modifiable factor in cognitive aging should consider both ANS branch’s effects simultaneously, particularly in the early stages of midlife. [1]: https://www.icpsr.umich.edu/icpsrweb/ICPSR/series/203