Following mechanical milling, the condensation reaction of the corresponding heterocyclic aldehydes with Isoniazid yields the Schiff base (E)‐N′‐((1H‐pyrrol‐2‐yl) methylene)isonicotinohydrazide (S1) and (E)‐N′‐(Thiophen‐2‐ylmethylene)isonicotinohydrazide (S2) supported heterocyclic derivatives. The structures of the Schiff bases, S1 and S2 were confirmed by 1H NMR, 13C NMR and IR spectroscopy. Copper ions (Cu2+) were trapped by S1 in DMSO to form the yellow‐coloured complex Cu‐(E)‐N′‐((1H‐pyrrol‐2‐yl)methylene) isonicotinohydrazide (Cu2++S1) with high sensitivity and selectivity. But the same ligand S1 could not be able to capture other metal ions tested for this work (namely, Co2+, Ni2+, Zn2+, Mn2+, Hg2+, Cd2+, Pb2+, Fe2+, and Fe3+) in DMSO. UV‐visible spectroscopic results confirmed the complex formation (Cu2++S1) with copper ions, but not with the other ions. Analysis of non‐covalent interactions (NCI) of ligand S1 with Ni2+, Cu2+ and Zn2+ in DMSO were investigated by density functional theory (DFT). NCI analysis of S1 by Cu2+ ions in DMSO was in good agreement with the experimental results. S2 did not react with any metal ions used in this study to form a complex in DMSO and the same was confirmed by UV‐Visible spectra. Reasonably good antibacterial activity was observed with S1, S2, Cu2++S1 compared to amoxicillin against Gram‐negative bacteria (K. pneumoniae, E. coli), Gram‐positive bacteria (S. aureus, S. pneumoniae), and fungal strain (C. albicans).