In the present study, the synthesis of six new Ni(II) and Pd(II) complexes with three derived sulfamethoxazole drug ligands is reported. The coordination mode, geometry, and chemical formula of all the synthesized compounds have been determined by elemental analysis, mass spectrometry, emission atomic spectroscopy, conductivity measurements, magnetic susceptibility, FTIR, TGA, H-NMR, electronic absorption spectroscopy, SEM-EDX along with DFT calculations. The Schiff Base ligands were found to be bidentate and coordinated to the metal ions through sulfonamidic nitrogen and oxazolic nitrogen atoms leading to a square planar geometry for palladium (II) while a distorted octahedral geometry around Nickel (II) ion was suggested. Biological applications of the new complexes including in vitro antimicrobial, antioxidant and anticancer properties were investigated. The results showed that the new metal (II) compounds exhibit remarkable antibacterial inhibition activity against both Gram-positive and Gram-negative bacteria, in addition to noticeable DPPH free radical scavenging activity. The in vitro cytotoxicity assay of the complexes against cell lines of chronic myelogenous leukaemia (K562) showed promising potential for the application of the coordination compounds in antitumor therapy. Subsequently, to evaluate the pharmaceutical potential of the metal-containing compounds, pharmacokinetics and toxicity were studied by ADMET simulations while interactions between the complexes and bacterial proteins were evaluated by molecular docking.