Background: It is well known that vigorous physical activity induces functional changes in cardiac autonomic nervous system (ANS) activity that is sustained several hours after exercise. However, data related to ANS recovery after more extreme endurance events, such as skyrunning marathons, are still lacking. Objective: The aims of this prospective cohort study were firstly, to determine the ANS response to a SkyMarathon, and secondly, to examine correlates of run performance. Methods: Ten male skyrunners aged 37.2 ± 9.2 years were recruited. The race was performed at a mean intensity 85.4 ± 3.7% of heart rate reserve, and lasted for 338 ± 38 min. Morning supine heart rate variability was measured at 10, 2 and 1 days before race, on the race day, at 5 min intervals for 30 min immediately post-race and then at 5 h and 30 h post. High-frequency power (HF, 0.15–0.50 Hz), low-frequency power (LF, 0.05–0.15 Hz), and square root of the mean of the squares of the successive differences (RMSSD) were calculated and transformed by natural logarithm (Ln). Results: Sympathovagal balance (Ln LF/HF) was most likely increased above baseline during the 30 min post-race and returned to baseline by 5 h. Vagal activity (Ln RMSSD and Ln HF) was most likely decreased below baseline during the 30 min post-race and 5 h of post-race, and recovered to baseline by 30 h. Race time correlated with resting heart rate (r =.81), body mass index (r =.73), maximal power output (r = –.70), and maximal oxygen uptake (r = –.61). Conclusions: The SkyMarathon elicited disturbances in ANS activity, with relative sympathetic activity increased up to 5 h post-race and vagal activity recovering by 30 h. Resting heart rate, body mass index, maximal power output, and maximal oxygen uptake were associated with SkyMarathon performance prediction.