Background Manual compression (MC) is the current standard to achieve post-procedural hemostasis in patients who need venous vascular access closure after cardiovascular procedures. Figure-of-8 (F8) suture for venous access closure has been reported to be a safe and efficacious alternative to MC. Methods A systematic search was done using PubMed, Google Scholar, EMBASE, SCOPUS and ClinicalTrials.gov without language restriction up until April 15, 2020 for studies comparing F8 suture vs MC. Risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI) were calculated using a random effects model. Results Time to achieve hemostasis was significantly reduced in the F8 arm [MD -21.04 mins (95% CI: -35.66 to -6.42; p=.005)]. Access site bleeding was significantly lower in the F8 group [RR 0.35 (95% CI: 0.18 to 0.66; p=0.001)] along with a lower incidence of hematoma formation [RR 0.42 (95% CI 0.26 to 0.67; p=0.0003)]. There was no significant difference in rates of fistula or pseudoaneurysm formation between the two groups. Overall access site complications were lower in the F8 arm [RR 0.38 (95% CI: 0.26 to 0.55; p<0.00001)] and the effect was more pronounced for sheaths ≥10 Fr [RR 0.33 (95% CI: 0.18 to 0.60; p=0.0003)]. There was lower post-procedural protamine use in the F8 group [RR 0.07 (95% CI:0.01 to 0.36; p=0.001)]. Conclusion For large-bore venous access closure, the F8 suture results in a shortened time to achieve hemostasis along with a lower overall risk of access site complications and post-procedural protamine use.