Novel thiophene-derived Schiff base ligand DE, where DE is (E)-N 1 ,N 1 -diethyl-N 2 -(thiophen-2-ylmethylene)ethane-1,2-diamine, and the corresponding M(II) complexes, [M(DE)X 2 ] (M = Cu or Zn, X = Cl; M = Cd, X = Br), were prepared and structurally characterized. X-ray diffraction studies revealed that the geometry around the center of the M(II) complexes, [Zn(DE)Cl 2 ] and [Cd(DE)Br 2 ], could be best described as a distorted tetrahedral. In vitro antimicrobial screening of DE and its corresponding M(II) complexes, [M(DE)X 2 ], was performed. The complexes were more potent and showed higher activities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, fungi Candida albicans, and protozoa Leishmania major compared to the ligand. Among the studied complexes, [Cd(DE)Br 2 ] exhibited the most promising antimicrobial activity against all the tested microbes compared to its analogs. These results were further supported by molecular docking studies. We believe that these complexes may significantly contribute to the efficient designing of metal-derived agents to treat microbial infections.