Exploring materials with high thermoelectric (TE) performance can alleviate energy pressure and protect the environment, and thus, TE materials have attracted extensive attention in the new energy field. In this paper, we systematically study the TE properties of Tl2S3 using first-principles combined with Boltzmann transport theory (BTE). The calculation results show an excellent power factor (1.12 × 10-2 W m-1 K-2) and ultra-low lattice thermal conductivity (kl = 0.88 W m-1 K-1) at room temperature. Through analysis, we attribute the ultra-low kl of Tl2S3 to the lower phonon group velocity (vg) and larger phonon anharmonicity. Meanwhile, discussion of chemical bonding showed that the filling of the anti-bonding state leads to the weakening of the Tl-S chemical bond, resulting in low vg. Furthermore, this research also investigates the scattering processes (the out-of-plane acoustic mode (ZA) + optical mode (O) → O (ZA + O → O), the in-plane transverse acoustic mode (TA) + O → O (TA + O → O), and the in-plane longitudinal acoustic mode (LA) + O → O (LA + O → O)), from which we find that 2D Tl2S3 possesses strong acoustic-optical scattering. Based on the analysis of electron transport properties under electron-phonon coupling, 2D Tl2S3, as a novel TE material, exhibits a ZT value as high as 2.8 at 400 K. Our calculations suggest that Tl2S3 is a potential TE material at medium temperature.