Mechanochemistry has recently emerged as an environmentally friendly solventless synthesis method enabling a variety of transformations including those impracticable in solution. However, its application in the synthesis of well‐defined nanomaterials remains very limited. Here, we report a new bottom‐up mechanochemical strategy to rapid mild‐conditions synthesis of organic ligand‐coated ZnO nanocrystals (NCs) and their further host–guest modification with β‐cyclodextrin (β‐CD) leading to water‐soluble amide‐β‐CD‐coated ZnO NCs. The transformations can be achieved by either one‐pot sequential or one‐step three‐component process. The developed bottom‐up methodology is based on employing oxo‐zinc benzamidate, [Zn4(μ4‐O)(NHOCPh)6], as a predesigned molecular precursor undergoing mild solid‐state transformation to ZnO NCs in the presence of water in a rapid, clean and sustainable process.