We conducted a systematic review and meta-analysis to assess the clinical efficacy of high-flow nasal cannula (HFNC) therapy as apneic oxygenation in critically ill patients who require endotracheal intubation in the intensive care unit (ICU). This systematic review and meta-analysis included six randomized controlled trials and a prospective study identified in PubMed, Embase, Cochrane Library, and the Web of Science until August 18, 2019. In this meta-analysis including 956 participants, HFNC was noninferior to standard of care during endotracheal intubation regarding incidence of severe hypoxemia, mean lowest oxygen saturation, and in-hospital mortality. HFNC significantly shortened the ICU stay by a mean of 1.8 days. In linear meta-regression interaction analysis, the risk ratio of severe hypoxemia decreased with increasing baseline partial oxygen pressure (PaO2) to fraction of inspired oxygen (FiO2) ratio. In subgroup analysis, HFNC significantly reduced the incidence of severe hypoxemia during endotracheal intubation in patients with mild hypoxemia (PaO2/FiO2> 200 mmHg; risk difference, -0.06; 95% confidence interval, -0.12 to -0.01; number needed to treat = 16.7). In conclusion, HFNC was noninferior to standard of care for oxygen delivery during endotracheal intubation and was associated with a significantly shorter ICU stay. The beneficial effect of HFNC in reducing the incidence of severe hypoxemia was observed in patients with mild hypoxemia.