Background <p>To systematically evaluate the effect of tranexamic acid (TXA) on the incidence of heterotopic ossification (HO) following orthopedic surgery.</p> Methods <p>A Systematic review and Meta-analysis was carried out according to PRISMA guidelines. PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched from inception date to October 15, 2025. Randomized controlled trials (RCTs) and observational studies comparing TXA with control (placebo or no TXA) in patients undergoing orthopaedic surgery who reported rates of HO were included. Data were pooled using a random-effects model, and subgroup and sensitivity analyses were performed.</p> Results <p>Six studies involving 1456 patients (TXA = 778, Control = 678) were included. All included studies reported HO outcomes. When stratified by study design, pooled analysis of randomized controlled trials (RCTs) showed no significant reduction in HO incidence with TXA (OR = 0.92, 95% CI 0.11–7.77; I² = 55.3%). In contrast, observational studies demonstrated a significant association between TXA use and reduced HO incidence (OR = 0.59, 95% CI 0.45–0.77; I² = 0%). Safety outcomes were reported in only one study. No statistically significant differences were observed between the TXA and control groups in the incidence of deep vein thrombosis, pulmonary embolism, or wound infection.</p> Conclusions <p>Current evidence does not demonstrate a statistically significant reduction in heterotopic ossification with tranexamic acid based on randomized data. Although observational studies suggest a potential association, this finding may be influenced by confounding and should be interpreted with caution.</p>