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Introduction Prone positioning in mechanically ventilated patients with severe acute respiratory distress syndrome (ARDS) is associated with improved mortality. More data is needed to fully understand its utility in those with ARDS due to COVID-19. Methods We conducted a single center prospective observational study inclusive of 100 consecutive patients intubated for ARDS from COVID-19 admitted to the ICU from September 2020 to December 2020. Data was collected daily from time of intubation for 7 days along with 30-day outcomes. Results The study included a total of 53 patients proned and 47 non-proned during their hospitalization. Proned patients were 61.8 years old, and 56.6% men compared to 66.3 years old and 57.4% male in the non-proned group. Other baseline characteristics and treatments were similar between both groups other than proned patients having a higher BMI than non-proned patients (34.1 ± 7.5 vs 30.5 ± 7.4, p = 0.02), and lower initial P/F ratios (119.1 ± 54.5 vs 154.0 ± 92.7, p = 0.047). Proned patients required more neuromuscular blockade (OR 6.63, 95% CI 3.25–13.12, p < 0.0001) and higher sedation levels (2 sedatives: OR = 3.00, 95% CI = 1.77,5.08; ≥3 sedatives: OR = 7.13, 95% CI = 3.96,12.81) with similar ICU length of stays, ventilator days, newly initiated renal replacement therapy, and 30-day outcomes when compared to non-proned patients. Proned patients were re-intubated substantially less than the non-proned group (1.9% vs 19.1%, p = 0.006). Conclusion Proning mechanically ventilated COVID-19 patients was associated with more frequent use of neuromuscular blockade and sedation, and required significantly lower rates of re-intubation for respiratory failure when compared to non-proned patients.