The study of structural isomerism in copper nanoclusters has been relatively limited compared to that in gold and silver nanoclusters. In this work, we present the controlled synthesis and structures of two isomeric copper nanoclusters, denoted as Cu22-1 and Cu22-2, whose compositions were determined to be Cu22(SePh)10(Se)6(P(Ph-4F)3)8 through single-crystal X-ray diffraction (SCXRD). The structural isomerism of Cu22-1 and Cu22-2 arises from the different arrangements of a few Cu(SeR)(PR3) motifs on the surface structure. These subtle changes in the surface structure also influence the distortion of the core and the spatial arrangement of the clusters, and affect the electronic structure. Furthermore, due to their distinct structures, Cu22-1 and Cu22-2 exhibit different catalytic properties in the copper-catalyzed [3 + 2] azide-alkyne cycloaddition (CuAAC). Notably, Cu22-1 demonstrates efficient catalytic activity for photoinduced AAC, achieving a yield of 90% within 1 hour. This research contributes to the understanding of structural isomerism in copper nanoclusters and offers insights into the structure-function relationship in these systems.