Uric acid (2,6,8-Trihydroxypurine, UA) is the end product of purine metabolism in human. In a healthy man, the normal level of UA in urine is in mM range where as in serum it is in µM range. So far, many electrochemical sensors have been developed for the UA determination but the interferential species such as ascorbic acid (AA) and dopamine (DA) have greatly affected the UA oxidation due to their similar electroactive properties. In this work, highly sensitive, selective and reproducible electrochemical UA sensors was proposed, using graphene (Gr) sheets, Cu(II)-polydopamine (PDA) complex and Cu nanoparticles (denoted as CuNPs/Cu(II)-PDA/Gr). In particular, a Geometry, Frequency, Non-covalent, eXtended Tight Binding (GFN2-xTB) and Density Functional Theory (DFT) studies were performed to provide reasonable explanations of reactive/catalytic sites, the interaction as well as structure of CuNPs/Cu(II)-PDA/Gr. The key role of each individual component in the sensing interface was thoroughly discussed and closely correlated with theoretical quantum calculations. To our best knowledge, this is the first study reporting not only such a simple however best performing design for electrochemical UA sensor (wide linear range, low detection limit, excellent selectivity, reproducibility) but also the application of GFN2-xTB, DFT quantum calculations in elucidating the working principle of the each component as well as the whole sensor.