Significance: Pulse oximetry is widely used in clinical practice to monitor changes in arterial oxygen saturation (SpO2). However, decreases in SpO2 can be delayed relative to the actual clinical event, and near-infrared spectroscopy (NIRS) may detect alterations in oxygenation earlier than pulse oximetry, as shown in previous cerebral oxygenation monitoring studies. Aim: We aim to compare the response of transcutaneous muscle NIRS measures of the tissue saturation index with pulse oximetry SpO2 during hypoxia. Approach: Episodes of acute hypoxia were induced in nine anesthetized Yucatan miniature pigs. A standard pulse oximeter was attached to the ear of the animal, and a transcutaneous NIRS sensor was placed on the hind limb muscle. Hypoxia was induced by detaching the ventilator from the animal and reattaching it once the pulse oximeter reported 70% SpO2. Results: Twenty-four episodes of acute hypoxia were analyzed. Upon the start of hypoxia, the transcutaneous NIRS measures changed in 5.3 ± 0.4 s, whereas the pulse oximetry measures changed in 14.9 ± 1.0 s (p textless 0.0001). Conclusions: Transcutaneous muscle NIRS can detect the effects of hypoxia significantly sooner than pulse oximetry in the Yucatan miniature pig. A transcutaneous NIRS sensor may be used as an earlier detector of oxygen saturation changes in the clinical setting than the standard pulse oximeter.