This article presents the results of transferring a high-performance liquid chromatography (HPLC) procedure for the assay of amoxicillin and potassium clavulanate in tablets to the ultra-performed liquid chromatography (UPLC) conditions. Since the State Pharmacopoeia of Ukraine (SPhU) does not contain the monograph for the simultaneous analysis of amoxicillin and clavulanic acid, the British Pharmacopoeia procedure was used. Parameters of the procedure were optimized to fit the UPLC and to make a better performance. Transfer of the method to the UPLC conditions allowed to shorten the run time from 15 min to 7.5 min, which makes the process less time-consuming and more cost-effective. The upgraded procedure was further validated. Validation of both methods was performed in terms of linearity, precision, accuracy, specificity and stability. HPLC method was verified to later implementation into the SPhUs monograph. Afterwards, the methods were compared in terms of their impact on the environment using the eco-scale that included hazards of the solution, the amount of produced wastes, the impact on environmental and laboratory staff, etc. Both methods appeared to be eco-friendly with a moderate advantage of UPLC method. Moreover, the statistical comparison was performed using Passing Bablok regression method. It showed that both methods are statistically comparable.