Tranexamic acid (TXA) effectively reduces blood loss and transfusion risk during total joint arthroplasty. Additionally, intraoperative irrigation with various antiseptic solutions is often utilized for the management and prevention of surgical site infection. However, interactions between various antiseptic solutions and TXA have not been investigated. The purpose of this in vitro study is to evaluate the stability of TXA in the presence of common orthopedic antiseptic solutions. Five antiseptic solutions—0.1% chlorhexidine (CHX) gluconate, 10% povidone-iodine (BTD), 0.5% sodium hypochlorite (Dakin's), 3% hydrogen peroxide (H₂O₂), and 1.5% H₂O₂—and a 0.9% normal saline (NS) control were obtained. A stock 100 mg/ml TXA solution was diluted in each antiseptic solution to a concentration of 10.0 mg/ml to generate reference standard and stability samples. TXA stability in each solution was measured using high performance liquid chromatography at t = 0 and t = 120 min and reported as mean percent of theoretical concentration (MPT) with associated relative standard deviation (RSD). All experiments were performed in triplicate at room temperature. At t = 0 min, TXA remained stable when mixed with 0.9% NS, 0.1% CHX, 10% BTD, 3% H₂O₂, and 1.5% H₂O₂ (MPT range:​ 102.0%−105.0%, RSD range:​ 0.80%−2.92%). Only 0.5% Dakin's led to significant degradation of TXA at t = 0 min (MPT:​ 14.3%, RSD:​1.28%). At t = 120 min, TXA stability persisted for all compounds except Dakin's 0.5% (MPT:​ 18.4%, RSD:​ 28.7%). TXA efficacy may be significantly diminished when 0.5% Dakin's is used as an intraoperative irrigation solution. CHX, BTD, and H₂O₂ do not degrade TXA.