The syndesmotic screw (SS) and suture button (SB) fixation methods are both widely used for the reduction of ankle syndesmotic injury, with varying outcomes. To review recently published randomized controlled trials (RCTs) to assess the outcomes between SS and SB fixation for ankle syndesmotic injury. Systematic review; Level of evidence, 1. The PubMed, Embase, ClinicalTrials.gov, and Cochrane databases were searched for relevant RCTs published between 1966 and 2021 according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Eligible studies were RCTs comparing SS and SB fixation for ankle syndesmotic injury. The risk of bias was evaluated using the Cochrane Risk of Bias tool. Primary outcomes included complications, malreduction, and unplanned reoperation, and secondary outcomes were the American Orthopaedic Foot & Ankle Society (AOFAS) score, Olerud-Molander ankle score (OMAS), and EuroQol-5 Domain (EQ-5D) score. The mean difference (MD) and risk ratio (RR) were calculated for continuous and dichotomous outcomes, respectively. Random- or fixed-effects model was applied according to heterogeneity. Of 389 studies, 8 RCTs involving 512 patients were included. Overall, 257 patients received SS fixation and 255 patients received SB fixation. The 2 groups did not differ significantly in malreduction (RR, -0.06; 95% CI, -0.18 to 0.07) or EQ-5D (MD, 0.01; 95% CI, -0.01 to 0.03). However, the SB group showed significant advantages over the SS group in complications (RR, 0.42; 95% CI, 0.26 to 0.66), unplanned reoperation (RR, 0.62; 95% CI, 0.43 to 0.89), AOFAS score (MD, 3.04; 95% CI, 1.77 to 4.31), and OMAS (MD, 4.51; 95% CI, 1.54 to 7.48). The risk of bias of the included studies was acceptable. The results showed that there were no significant differences between the SS and SB groups in malreduction and EQ-5D scores. However, the SB group had significantly better local irritation rates, unplanned reoperation rates, AOFAS scores, and OMASs.