Successful synthesis by vertical solidification (Bridgman - Stockbarger) technique is reported for a centimetre size noncentrosymmetric TlSbP2Se6 crystal (for the first time) with excellent transparency at 0.75–10 μm that is very useful for its practical application. The high homogeneity and stoichiometric composition have been confirmed by SEM-EDX. Next we determined the crystal structure, electronic properties by use of both experimental and theoretical methods. The layered structure of the crystal provides strong anisotropy of physical properties. Special attention was placed for an explanation of the source of the layer architecture and its effect on the strong anisotropy of properties. In particular, employing the XPS method, we have measured for the TlSbP2Se6 crystal the binding energies of core-level electrons as well as energy distribution of the valence electrons for both pristine and treated with Ar+ ions surfaces and shown that the TlSbP2Se6 crystal surface is highly hygroscopic. For interpretation and explanation of the measured XPS valence band spectrum, we examined different approaches for exchange correlation (XC) potential with a density functional theory (DFT) framework and found that the best agreement of the shapes of the XPS spectrum and the curve of total density of states is derived when the band structure calculations were made employing for XC potential modified Becke-Johnson (mBJ) functional in the form of Tran and Blaha. Based on the results of XPS measurements and calculations, we explained the contributions of individual ions to the band structure and convincingly demonstrated that ionic components of the chemical Sb–Se (P–Se) bonds in the TlSbP2Se6 crystal are similar to those of its silver-bearing counterpart AgSbP2Se6. The present DFT calculations within TB-mBJ + U + SO approach reveal that the TlSbP2Se6 compound is a non-direct semiconductor with Eg = 1.765 eV confirmed by UV-VIS measurements (1.75 eV). The main optical constants are explored in detail for TlSbP2Se6, as based on TB-mBJ + U + SO calculations. Finally, the result of the XPS investigations of the crystal surface after treatment with Ar+ ions supported by the calculations of the structure indicates its high chemical and mechanical resistance, which, despite the dangerous element contained in the composition, indicates its safe use in optoelectronic devices.