Experimental methods (NMR spectroscopy and X-ray diffraction) and quantum chemical calculations based on density functional theory (DFT) were used for structural and electronic characterization of two thiazolidine-2-thione-4-one derivatives with antimicrobial activity, namely 5- para-bromo-benzylidene-thiazolidine-2-thione-4-one (5pBr-BTT) and 5- para-fluoro-benzylidene-thiazolidine-2-thione-4-one (5pF-BTT). X-ray diffraction technique indicates that 5pBr-BTT crystallizes with one DMSO solvent molecule, forming a 1:1 5pBr-BTT·DMSO complex, in the triclinic space group P 1 ¯ , with Z = 2 and cell parameters a = 4.4597(7) Å, b = 12.5508(19) Å, c = 13.7270(2) Å, α = 90.75(2)°, β = 96.23(2)° and γ = 97.86(3)°. The linear conformation adopted in the crystalline state is established by intermolecular hydrogen bonds formed between oxygen atoms from DMSO and the thione group. 5pF-BTT crystallizes in the monoclinic space group P2 1/ c with Z = 4 and cell parameters a = 4.9161(4) Å, b = 19.9008(17) Å, c = 10.4934(9) Å and β = 92.90(2)°; these molecules form a wave-like arrangement along the c axis, with direct intermolecular hydrogen bonds (HBs). The lowest energy optimized geometries of the investigated compounds in gas-phase correspond to thionic tautomers and they are consistent with those obtained by X-ray technique. Tautomeric equilibrium between the thione, thiol and enol forms of the two compounds have been considered and analyzed by theoretical methods. While crystal structures correspond to the thione forms, the investigated compounds show thione–thiol tautomerism in DMSO solution, this conclusion being supported by theoretical results obtained by using the PCM solvation model. On the other hand, the continuum PCM solvation model fails to describe the experimental chemical shift associated with the NH proton in the thione form of the two compounds, but a very good correlation between experiment and theory was obtained by taking into account the specific solute–solvent interactions.