Gustilo 3 lower limb fractures represent a significant challenge because of high complication risk. Two management strategies are commonly used for wound coverage until final closure: negative pressure wound therapy (NPWT) and conventional wound dressing (CWD), also described as standard wound coverage without subatmospheric pressure. Understanding their relative effectiveness is essential to improve patient outcomes. The aim of this systematic review and meta-analysis was to compare the efficacy of NPWT and CWD in Gustilo 3 lower limb fracture management, with a focus on overall rates, superficial infection, and deep infection rates. A systematic review of medical research databases was conducted in accordance with PRISMA guidelines. Studies comparing NPWT with CWD for Gustilo 3 fractures were included. Data extraction and quality assessment were performed. Treatment with CWD was associated with significantly higher rates of overall infection [pooled risk ratio (RR): 0.33; 95% confidence interval (CI): 0.14-0.51] and pooled risk difference (RD: 0.27; 95% CI: 0.15-0.38), superficial infection (pooled RR: 0.35; 95% CI: 0.04-0.66), and deep infection (pooled RR: 0.20; 95% CI: 0.02-0.38) compared with NPWT treatment. Overall infection rate remained significantly higher in the CWD group after analyzing only open tibia fractures (pooled RR: 0.35; 95% CI: 0.21-0.48). Nonunion rate was significant higher in the CWD group (pooled RR: 0.30; 95% CI: 0.00-0.59). Flap failure rate was similar in both groups (pooled RR: 0.09; 95% CI: -0.05 to 0.23). NPWT appears to be a reasonable option for wound management in Gustilo 3 lower limb fractures in terms of infection rates.