Hypercapnic acute respiratory failure (ARF) is a life-threatning condition and a leading cause of hospital admission, mainly in acute exacerbation of chronic obstructive pulmonary disease (COPD). Although non-invasive ventilation (NIV) currently represents the first-line ventilatory strategy in patients exhibiting hypercapnic ARF, NIV may fail primarily due to worsening of ARF, patient-ventilator asynchrony, interface intolerance, even cardiovascular instability. Consequently, the operating principles and physiological effects of HFNC could be interesting and useful for applying this technique to the management of hypercapnic ARF. Therefore, from a clinical point of view, HFNC could be used alone continuously as an alternative to standard oxygen therapy or NIV, either at the initial phase of hypercapnic ARF or after extubation. In addition, according to the severity and etiology of the underlying hypercapnic ARF, HFNC could also be used in combination with NIV during breaks of spontaneous breathing. In this narrative review, we aimed therefore to provide an updated overview of the physiological rationale and clinical evidence for using HFNC in patients with hypercapnic ARF, with a particular focus on acute exacerbations of COPD.