Heat and moisture exchangers (HMEs) are commonly used during general anesthesia to provide appropriate humidification and warming of inspired gases. While they play a critical role in mechanical ventilation, they can also lead to acute difficult ventilation if not correctly monitored and drained. We present a case of a 56-year-old female patient who underwent lower extremity vascular bypass surgery under general anesthesia and experienced sudden increased airway pressures due to occlusion of the HME caused by excessive moisture accumulation. Proper monitoring and management of the airway circuit and HMEs can help prevent complications and ensure proper ventilation during surgery. When acute difficult ventilation is encountered during general anesthesia, a systematic approach should be taken to differentiate between patient and external factors. Other differential diagnoses for acute difficult ventilation include bronchospasm, aspiration, endotracheal tube misplacement, pulmonary embolism, and tension pneumothorax. HME occlusion should be considered as part of the differential diagnosis for intraoperative hypoxia. Proactive replacement of HMEs in long cases can prevent occlusion and ensure proper ventilation.