In this work, a new metal–organic framework nanocatalyst (Cu@UIO-66-AST) has been prepared from UiO-66-NH2 through a post-synthesis modification process. The Cu (II)@UIO-66-AST nanocatalyst formation was confirmed from TGA, FT-IR, TEM, XRD, BET, CHN, ICP, SEM, EDS, and elemental analyses. The catalytic efficiency of the synthesized MOF (Cu@UIO-66-AST), as an acid Lewis, was investigated in the four-component reaction of isatin, malononitrile, hydrazine, and dimethyl acetylene dicarboxylate and compared to UiO- 66-NH2 (as a basic catalyst) and Cu (OAc)2 (as an acidic heterogeneous catalyst). The obtained results clearly show that Cu@UIO-66-AST has a higher catalytic activity (93%) than UiO-66-NH2 (13%) and Cu (OAc)2 (43%). It could be due to the increase of dispersibility of Cu2+ by the formation of several stable complexes between Cu2+ ions and functional groups of ligand AST (OH, C=N, NH, and C-S) on the surface of the nanocatalyst. Also, the catalyst can be recycled and reused for up to eight subsequent runs without significant loss of activity.