 6-Thioguanine (6-TG) drug is commonly used for the treatment of inflammatory bowel disease, acquired immune deficiency syndrome, Crohn’s disease, and childhood acute lymphoblastic leukaemia. However, a high dose of 6-TG may cause severe side effects, including bone marrow depression and gastrointestinal complications. Two-dimensional nanomaterials have attracted the attention of researchers as chemical sensors for different biological molecules. Here, density functional theory calculations were performed to explore the interaction properties of 6-TG with a silicon carbide monolayer (SiCM) as well as noble metal (Au)-decorated SiCM (Au@SiCM) to elaborate on their potential application as electronic sensors. The sensing response of the SiCM to the 6-TG drug is very small (~ 3.9 at 298 K) because of a weak interaction with adsorption energy and charge transfer of − 0.15 eV and 0.03 |e|, respectively. An Au atom was preferentially adsorbed above a Si-C bond of the SiCM, releasing the energy of 3.79 eV. By the Au decoration, the 6-TG was strongly adsorbed onto the Au@SiCM with adsorption energy of − 0.79 eV and the sensing response increased to 384.0. The recovery time for the 6-TG desorption from the Au@SiCM surface was obtained to be 2.3 s. Consequently, the Au@SiCM can transform the existence of 6-TG molecules into electrical signals and it may potentially be applied as an electronic sensor for the recognition of the 6-TG drug.