The aim of this study was to construct hydrogenated two-dimensional cu-bic atomic diamonds with hydrogen vacancy-hydrogenated cubic diamond (Hv-HCD) and without hydrogen vacancy (HCD). Furthermore, the isolated monolayer of hexagonal boron nitride (h-BN) or graphene (G) and Hv-HCD were reassembled into van de Waals het-erostructures, h-BN/Hv-HCD, and G/Hv-HCD. Based on first-principles, the Fukui func-tions of water, indoxyl sulfate, and the constructed hydrogenated two-dimensional cubic atomic diamonds with hydrogen vacancy were calculated. The largest values of f+(r) and f−(r) lie around the carbon atom close to the hydrogen vacancy, implying that the carbon atom was the nucleophilic and electrophilic reactive site. The results indicate that a water molecule forms a hydrogen bond with the carbon atom close to the hydrogen vacancy of the hydrogenated two-dimensional atomic diamonds with hydrogen vacancy. The indoxyl phosphate molecule is degraded into 3-indolone and sulfur dioxide at the carbon atom close to the hydrogen vacancy site. The hydroxyl in the sulfonic group forms an alcoholic hy-droxyl with the carbon atom close to the hydrogen vacancy. The phenomena described here could provide a foundation for investigating the essential materials for the development of bioactive or human blood toxic molecule sensors based on two-dimensional atomic crystals.