Background <p>The use of tranexamic acid (TXA) in breast surgery, specifically, gender-affirming mastectomy, has gained traction within the past two years. Its efficacy, however, has not been fully elucidated. The goal of this study is to synthesize current literature of TXA on postoperative outcomes in gender-affirming mastectomy.</p> Methods <p>A systematic review was conducted following PRISMA guidelines. PubMed, MEDLINE, CENTRAL, Scopus, and Web of Science were queried to identify studies documenting TXA application in gender-affirming mastectomy. A multi-screener approach was utilized to select pertinent studies for full-text screening. Outcomes included hematoma, seroma, nipple-areola complex (NAC) necrosis, surgical site infection (SSI), drain output, drain duration, and thromboembolic events. Following pooling of data, a meta-analysis was performed using odds ratios (OR) via the Mantel-Haenszel method.</p> Results <p>Six studies with a total of 2,743 patients were included, with 42.1% (1,156) receiving TXA. Intraoperative administration of TXA was reported in all patients, with 40.7% (471) receiving topical TXA and 59.3% (685) receiving intravenous TXA. TXA administration significantly reduced postoperative hematoma formation (OR 0.48; 95% CI [0.33–0.70]; <i>P</i> &lt; 0.001) and postoperative seroma formation (OR 0.66; 95% CI [0.49–0.89]; <i>P</i> = 0.007). Three articles reported data on drain output and drain duration, with discordant results. One thromboembolic event was reported in the TXA cohort, while there were no differences in outcomes based on route of TXA administration.</p> Conclusions <p>TXA administration in gender-affirming mastectomy safely reduces the odds of postoperative hematoma and seroma formation. Further research is needed to identify its impact on reducing drain output and drain duration. Level of Evidence: Not gradable</p>