Three facile, accurate, and eco-friendly spectrophotometric methods were developed for determination of the novel anticoagulant drug, betrixaban (BTX). The first method (method A) was based on the unique UV absorption spectrum of BTX, where direct analysis of BTX was performed at 229.4nm on the recorded zero order spectrum using methanol as the optimum solvent. While the second method(method B) was based on measuring difference absorption value(DA) of BTX at 335nm, which was obtained from pH-induced spectral difference (Difference spectra of BTX in 0.1M NaOH versus 0.1M HCl). The third mathematical spectrophotometric method (method C) was established for simultaneous analysis of BTX with the co-administered Ca channel blocker lercanidipine (LER). In this method, the first order derivative technique was utilized to resolve the overlapping UV spectra of both drugs. The first derivative amplitudes at 206nm and 229nm were used for quantitative assay of BTX and LER, respectively. All methods obeyed Beer’s law in the concentration ranges of 1.0–20.0µg.mL^-1 and 8.0–80.0 µg.mL^-1 for BTX in methods A and B, respectively, and of 1.0–20.0 µg.mL^-1 and 1.0–25.0µg.mL^-1 for BTX and LER, respectively in method C. The three methods were fully validated, and the results showed good agreement with the other compared ones where high %recoveries and low values of RSD (<1.5%) were obtained. Moreover, the green profile of the proposed methods was assessed by using two approaches: analytical eco-scale and green analytical procedure index. The results indicated that method B was the greenest one because hazardous organic solvents were avoided. Both methods A and C have analytical eco-scale scores of 85 which indicated the greenness of these methods as well. The absence of interferences that could be produced from encountered additives, excipients, or degradation products ensured the high specificity of the proposed methods and supported their applicability in quality control laboratories.