Multicenter, phase‐4, randomized, comparative‐efficacy study in patients with VLUs or DFUs comparing for noninferiority the percentage change in target ulcer dimensions (area, depth, and volume) a single‐use negative pressure wound therapy (s‐NPWT) system versus traditional NPWT (t‐NPWT) over a 12‐week treatment period or up to confirmed healing. Baseline values were taken at the randomization visit. Randomized by wound type and size, 164 patients with non‐infected DFUs and VLUs were included. The ITT population was composed of 161 patients (101 with VLUs, 60 with DFUs) and 115 patients completed follow‐up (64 in the s‐NPWT group and 51 in the t‐NPWT group) (PP population). The average age for all patients was 61.5 years, 36.6% were women, and treatment groups were statistically similar at baseline. Primary endpoint analyses on wound area reduction demonstrated statistically significant reduction in favor of s‐NPWT ( p = 0.003) for the PP population and for the ITT population ( p < 0.001). Changes in wound depth ( p = 0.018) and volume ( p = 0.013) were also better with s‐NPWT. Faster wound closure was observed with s‐NPWT (Cox Proportional Hazards ratio (0.493 (0.273, 0.891); p = 0.019) in the ITT population. Wound closure occurred in 45% of patients in the s‐NPWT group vs. 22.2% of patients in the t‐NPWT group ( p = 0.002). Median estimate of the time to wound closure was 77 days for s‐NPWT. No estimate could be provided for t‐NPWT due to the low number of patients achieving wound closure. Device‐related AEs were more frequent in the t‐NPWT group (41 AEs from 29 patients) than in the s‐NPWT group (16 AEs from 12 patients). The s‐NPWT system met noninferiority and achieved statistical superiority vs. t‐NPWT in terms of wound progression toward healing over the treatment period. When NPWT is being considered for the management of challenging VLUs and DFUs, s‐NPWT should be considered a first choice over other types of NPWT.