In nanobiotechnology, organic molecule-containing two-dimensional nano-structured materials are considered crucial for developing horizontal bio-inorganic nano-devices for pharmaceutical applications. We present a complete review of the application of silicon carbide monolayer (SiCML) for smart drug delivery of hydroxyurea (HU) through density functional theory computations. Also, interacting host-guest complexes with different approaching orientations, the charge transport, and the interaction strength were scrutinized. It was found that the application of HU together with SiCML was significantly effective for bio-functionalization with −35.86 kcal/mol interaction energy. The charge transfer from HU to the SiCML was confirmed by Hirshfeld method. The findings of the current study provide useful insights into research on the application of functionalized nano-biomaterials for drug delivery, nano-medicine, and other related fields.