To systematically review the literature to determine the prevalence and risk of the free flap and postoperative complications in scalp-free tissue reconstruction with synthetic mesh cranioplasty. Search strategies created with a medical librarian were implemented using multiple databases in May 2021. Two reviewers independently performed the review, data extraction, and quality assessment. Cohort studies of patients with scalp-free tissue reconstruction with or without mesh cranioplasty were included. Studies that did not report whether mesh was used or did not separate outcomes by mesh use were excluded. The primary outcomes were free flap failure and postoperative complications. A random-effects model was used for the meta-analysis to estimate prevalence and prevalence ratios (PRs). A total of 28 studies and 440 cases of scalp-free tissue reconstruction were included. The pooled prevalence of free flap failures and postoperative complications in patients with mesh cranioplasty was estimated at 7% (95% confidence interval [CI], 3%-17%; p = .85, I2  = 0%) and 21% (95% CI, 14%-31%; p = .44, I2  = 0%), respectively. In a subgroup analysis, mesh cranioplasty was not associated with a significantly increased risk of free flap failure or postoperative complications when compared to cases without mesh cranioplasty; pooled PR 1.21 (95% CI, 0.50-2.88; p = .90, I2  = 0%) for free flap failure and PR 1.85 (95% CI, 0.89-3.85; p = .28, I2  = 19) for postoperative complications. Synthetic mesh cranioplasty does not significantly increase the risk of free flap compromise or postoperative complications. A higher prevalence of postoperative recipient site complications was observed in patients with mesh cranioplasty.