Background: N, N-Dimethyltryptamine (N, N-DMT) is a naturally occurring tryptamine-based alkaloid and classic psychedelic. The potent psychoactive properties of N, N-DMT are mediated by serotonin 2A (5-HT2A) receptor agonism. There are limited investigations into the physiologic effects of inhaled N, N-DMT, despite this being one of the most common routes of administration. Heart rate variability (HRV) is an emergent non-invasive marker of cardiac autonomic nervous system (ANS) regulation and reductions in HRV have been negatively associated with multiple health outcomes. Methods: A case is described with a brief review of supportive findings. Results: Heart rate (HR) and HRV responses following three naturalistic inhaled N, N-DMT experiences were documented in a healthy 31-year-old male. Acute transient elevations in HR immediately following N, N-DMT administration and a pronounced elevation in the average daily HRV one-day following the experiences were observed. The duration of experience shortened across the three experiences despite similar N, N-DMT doses. Conclusion: These findings offer preliminary evidence into the effect of inhaled N, N-DMT on HR and HRV. Given the emergent understanding of reductions in HRV as a hazardous marker of stress, psychiatric conditions, and mental health outcomes, further research into the effects of psychedelics on HRV is warranted.