Intermittent right-to-left shunting through an atrial septal defect (ASD) is a rare but significant cause of acute hypoxic respiratory failure. This case highlights the diagnostic and management challenges associated with an intermittent interatrial shunt. A 65-year-old man presented with profound hypoxia requiring mechanical ventilation. Despite an extensive initial workup, including a computed tomography angiogram and transthoracic echocardiography with a bubble study, which was negative for an intracardiac shunt, no definitive cause for his hypoxia was identified. Given persistent clinical suspicion and the episodic nature of the isolated hypoxia, a transesophageal echocardiogram was performed, revealing a 2.6 cm² secundum ASD with intermittent right-to-left shunting, predominantly occurring during maneuvers that increased intrathoracic pressure, such as Valsalva. Key differentials, including pulmonary embolism and pneumonia, were systematically excluded. The patient underwent successful percutaneous ASD closure, leading to significant improvement in oxygenation, with follow-up demonstrating sustained normoxia and stable oxygen saturation. This case underscores the importance of considering an intracardiac shunt in patients with unexplained, episodic hypoxia and demonstrates the necessity of advanced imaging modalities for accurate diagnosis.