Density functional theory methods were employed to clarify the adsorption/desorption behaviors of the thione‐containing mercaptopurine and thioguanine drugs on the gold surface using both small Au6 and Au8 clusters as model reactants. Structural features, thermodynamic parameters, bonding characteristics, and electronic properties of the resulting complexes were investigated using the Perdew–Burke–Ernzerhof (PBE) and LC‐BLYP functionals along with correlation‐consistent basis sets, namely cc‐pVDZ‐PP for gold and cc‐pVTZ for non‐metals. Computed results show that the drug molecules tend to anchor on the gold cluster at the S atom with binding energies around −34 to −40 kcal/mol (in vacuum) and − 28 to −32 kcal/mol (in aqueous solution). As compared to Au8, Au6 undergoes a shorter recovery time and a larger change of energy gap that could be converted to an electrical signal for selective detection of the drugs. Furthermore, interactions between the drugs and gold clusters are reversible processes and a drug release mechanism was also proposed. Accordingly, the drugs are able to separate from the gold surface due to either a slight change of pH in tumor cells or the presence of cysteine residues in protein matrices.