Introduction: To identify characteristics associated with successful weaning from high-flow nasal cannula (HFNC) and survival in patients with coronavirus disease 2019 (COVID-19)—associated acute respiratory failure. Methods: In this retrospective, observational study performed at a tertiary care center in Mumbai, we evaluated patients with COVID-19-associated acute respiratory failure (C-ARF) who were managed with HFNC. The primary outcome was the proportion of patients who were successfully weaned from HFNC. Secondary outcomes were factors that influenced weaning and survival. Failure of HFNC was defined as those who required invasive ventilation after initial HFNC. Results: Respiratory rate-oxygenation (ROX) 6 was positively correlated to ROX24 (r = 0.5 and p < 0.0001), ROX48 (r = 0.44 and p < 0.0001), and ROX72 (r = 0.29 and p = 0.002). In multivariable logistic regression, average C-reactive protein (CRP) [odds ratio (OR) = 1.06, 95% confidence interval (CI): 1.008–1.12], average neutrophil to lymphocyte ratio (NLR) (OR = 1.04, 95% CI: 1.004–1.08), average platelet count (OR = 0.99, 95% CI: 0.99–0.999), and average fluid balance (OR = 1.01, 95% CI: 1.002–1.02) were associated with the need for intubation. Average NLR (OR = 1.04, 95% CI: 1.005–1.08) and average platelet count (OR = 0.99, 95% CI: 0.98–0.99) were associated with mortality. Conclusion: High-flow nasal cannula (HFNC) is a suitable option in patients with C-ARF. Prospective studies are needed to validate the associated variables for the need for invasive ventilation in this group of patients.