Aim To evaluate the effect of non-invasive positive pressure ventilation (NIPPV) on (1) metabolic, ventilatory, and hemodynamic responses; and (2) cerebral (Cox), respiratory, and peripheral oxygenation when compared with SHAM ventilation during the high-intensity exercise in patients with coexisting chronic obstructive pulmonary disease (COPD) and heart failure (HF). Methods and Results On separate days, patients performed incremental cardiopulmonary exercise testing and two constant-work rate tests receiving NIPPV or controlled ventilation (SHAM) (the bilevel mode—Astral 150) in random order until the limit of tolerance (Tlim). During exercise, oxyhemoglobin (OxyHb+Mb) and deoxyhemoglobin (DeoxyHb+Mb) were assessed using near-infrared spectroscopy (Oxymon, Artinis Medical Systems, Einsteinweg, The Netherlands). NIPPV associated with high-intensity exercise caused a significant increase in exercise tolerance, peak oxygen consumption ( V · O 2 in mlO 2 ·kg −1 ·min −1 ), minute ventilation peak ( V · E in ml/min), peak peripheral oxygen saturation (SpO 2 , %), and lactate/tlim (mmol/s) when compared with SHAM ventilation. In cerebral, respiratory, and peripheral muscles, NIPPV resulted in a lower drop in OxyHb+Mb ( p < 0.05) and an improved deoxygenation response DeoxyHb+Mb ( p < 0.05) from the half of the test (60% of Tlim) when compared with SHAM ventilation. Conclusion Non-invasive positive pressure ventilation during constant work-rate exercise led to providing the respiratory muscle unloading with greater oxygen supply to the peripheral muscles, reducing muscle fatigue, and sustaining longer exercise time in patients with COPD-HF.