INTRODUCTION Severe hypercapnia is a rare but harmful complication of general anesthesia. We report the case of a newborn who developed severe hypercapnia with unknown reasons during general anesthesia but recovered well. This report will advance our understanding about the causes of severe hypercapnia during anesthesia, the possible compensatory mechanisms and the characteristics of neonatal respiratory physiology and intracellular buffering systems. CASE PRESENTATION A 21-day-old Chinese baby girl who had an incarcerated hernia received an emergent exploratory operation under general anesthesia. She developed severe hypercapnia during surgery for unclear reasons. Arterial blood gas revealed a PCO2 of 149mmHg. Troubleshooting and relevant measures were taken, but the level of CO2 did not decrease. In spite of the high level of PCO2, the newborn recovered well without any complications. CONCLUSIONS Neonates are vulnerable to hypercapnia during anesthesia for their characteristic respiratory physiology. Heat and moisture exchange should be used with caution in newborns under general anesthesia as it can increase dead space. Intracellular buffering systems play an important role in tolerating severe hypercapnia. Although this case raised a great challenge to the homeostatic mechanism of the body, measures should be taken to maintain PCO2 values around the clinically acceptable level.