A green high performance liquid chromatographic method with ultra violet detector (HPLC-UV) is presented, for the first time, for the simultaneous estimation of two hepatoprotective drugs in capsules and spiked human plasma. The first component is a herbal supplement, namely silymarin (SR) and the second is vitamin E acetate (VE). The method utilized an isocratic elution using C8 column, a mobile phase consisting of methanol:acetonitrile:triethylamine:trifluoroacetic acid (85:15:0.2:0.1, by volume) at 1 mL/min flow rate and 210 nm as a measuring wavelength. All silymarin flavonolignans were measured together as a single peak. The method was evaluated for precision, selectivity, linearity, accuracy, LOQ, and LOD. SR and VE were detected in the linear range of 0.3–50 μg/mL and 0.1 to 50 μg/mL respectively. The Eco-scale score of the new HPLC method was 62 while it was 55 for the previous electrochemical method. Calibration curves had correlation coefficients of >0.999. The new method is better than the old electrochemical voltammetric method in terms of simplicity, greenness, wide linear range and analysis time.