Twelve new heteroleptic nickel(II) and copper(II) complexes of the type [M(L1–6)(Pfx)2] (1–12), where L1–6=2-benzylidenehydrazinecarbothioamide (L1), 2-benzylidene-N-methylhydrazinecarbothioamide (L2), 2-benzylidene-N-phenylhydrazinecarbothioamide (L3), 2-(4-methylbenzylidene)hydrazinecarbothioamide (L4), 2-(4-methylbenzylidene)-N-methylhydrazinecarbothioamide (L5) and 2-(4-methylbenzylidene)-N-phenylhydrazinecarbothioamide (L6), Pfx=pefloxacin and M=Ni(II) or Cu(II) have been synthesised, and their structures were confirmed by different spectral techniques. The spectral data and density functional theory (DFT) calculations supported the bonding of pefloxacin drug molecule via one of the carboxylate oxygen atoms and the pyridone oxygen atom, and the thiosemicarbazone ligand via the imine nitrogen and the thione sulfur atoms with the metal(II) ion, forming distorted octahedral geometry. In vitro antiproliferative activity of the synthesized complexes was evaluated against three human breast cancer (T47D, estrogen negative (MDA-MB-231) and estrogen positive (MCF-7)) as well as non-tumorigenic human breast epithelial (MCF-10a) cell lines, which showed the higher activity for the copper(II) complexes. The interaction of the synthesized complexes with an oncogenic protein H-ras (121 p) was explored by in silico molecular docking studies. Further, in silico pharmacokinetics and ADMET parameters were also analysed to predict the drug-likeness as well as non-toxic and non-carcinogenic behavior, and safe oral administration of the complexes.