Single crystals of CdTeMoO6 have been grown from its stoichiometric melts. CdTeMoO6 is non-hygroscopic and resistant to diluted HNO3 aqua-solution. It is also thermally stable up to 766 °C and thereafter melts congruently. Transmittance spectra of CdTeMoO6 show a broad transmittance window in the range of 345 nm to 5.4 μm. Based upon single-crystal X-ray diffraction analysis, CdTeMoO6 is nonpolar noncentrosymmetric (NCS) and features a neutral layered structure consisting of three types of NCS chromophores, i.e. TeO4 polyhedra with a stereoactive lone pair, distorted MoO4 tetrahedra, and regular CdO4 tetrahedra, the former two being counter-packed and the last one being nonpolar. Such a packing manner of the NCS chromophores is traditionally considered unfavorable to produce strong second-harmonic generation (SHG). However, powder SHG measurements reveal that CdTeMoO6 displays a remarkable SHG effect about 2 times that of polar KTiOPO4 (KTP) at 1.064 μm. The first-principles electronic structure and optical properties calculations have confirmed the presence of a strong SHG effect in CdTeMoO6, and have primarily revealed its origin.