Introduction Tranexamic acid (TEA) is used in reducing surgical blood loss. Literature shows no optimal regimen recommended for Bilateral Total Knee Arthroplasty (TKA). We evaluated three TEA regimens differing in dosage, timing and mode of administration in bilateral TKA to identify the most effective regimen to reduce blood loss. Methods We prospectively studied three TEA regimens (25 patients each) as follows: (1) two intraoperative, intravenous doses (IOIO), (2) two intraoperative local applications (LALA), and (3) one preoperative plus two intraoperative, intravenous doses (POIOIO). Two independent parameters of drain loss and total blood loss, calculated by the hemoglobin balance method were statistically evaluated. Results Mean drain loss was least (412.9 ml) in the POIOIO group, greatest (607.2 ml) in the IOIO group and LALA group in between (579.4 ml), with a statistically significant difference among them (p = 0.0022). On paired evaluation, the drain loss in the POIOIO group was significantly less as compared to the other two groups, whereas the difference between IOIO and LALA was not significant. Mean total blood loss was least in the POIOIO group (1207 ml) and greatest in LALA group (1270 ml). The difference among the groups was not statistically significant (p = 0.80). There was no incidence of any thromboembolic phenomenon. On correlation with our study on Most Effective Regimen in Unilateral TKA, both results were found to substantiate each other.