Importance Tranexamic acid (TXA) is increasingly used to minimize perioperative bleeding. However, its efficacy and safety profile across general surgical procedures remains unclear. Objective To evaluate the efficacy and safety of prophylactic TXA in reducing intraoperative blood loss, need for transfusion, and major bleeding in general surgery, while assessing its association with thromboembolic events and mortality. Data Sources PubMed, Embase, and Cochrane Library were systematically searched from inception to April 3, 2025. Study Selection Randomized clinical trials (RCTs) comparing TXA to placebo in adult patients undergoing general surgery and reporting at least 1 predefined outcome of interest were included. Data Extraction and Synthesis Two reviewers independently extracted data and assessed risk of bias. Mean differences (MDs) and risk ratios (RRs) with 95% CIs were pooled using random-effects models. Heterogeneity was assessed using the I 2 statistic. Results Twenty-six RCTs with a total of 6976 patients were included. TXA use was associated with lower intraoperative blood loss (MD, −35.85 mL; 95% CI, −57.20 to −14.51 mL; I 2 = 91%; P = .001), reduced need for transfusion (RR, 0.75; 95% CI, 0.60-0.94; I 2 = 54%; P = .01), and fewer major bleeding events (RR, 0.72; 95% CI, 0.59-0.89; I 2 = 0%; P = .002). No significant differences were found in venous thromboembolism (RR, 1.09; 95% CI, 0.62-1.92; I 2 = 15%; P = .75), mortality (RR, 1.08; 95% CI, 0.72-1.61; I 2 = 0%; P = .71), and length of stay (MD, −0.54 days; 95% CI, −1.15 to 0.06 days; I 2 = 73%; P = .08). In the subgroup analysis restricted to abdominal procedures, the benefits observed in the overall population on intraoperative blood loss and need for transfusion were no longer present. In the hepatobiliary subgroup, TXA was associated with a significant reduction in major bleeding (RR, 0.59; 95% CI, 0.39-0.90; I 2 = 0%; P = .01), while no significant differences were observed for the other outcomes. Conclusions and Relevance This systematic review and meta-analysis found that prophylactic TXA use was associated with lower intraoperative blood loss, transfusion requirements, and major bleeding without an observed increase in thromboembolic or mortality risk. Although these findings support the use of TXA in general surgery procedures, the decision to use TXA should be individualized considering individual patient characteristics and the specific procedure being performed.