Bi₂Te₃-based compounds are thermoelectric materials with the best performance near room temperature. The existence of a large number of complex defects makes defect engineering a core stratagem for adjusting and improving the thermoelectric performance. Therefore, understanding and effectively controlling the existence form and concentration of defects is crucial for achieving high-thermoelectric performance in Bi₂Te₃-based alloy. Herein, a series of Cl doped n-type quaternary Bi_2–x Sb_xTe_3–ySe_y compounds is synthesized by the zone-melting method. The correlation between defect evolution process and thermoelectric performance is systematically investigated by first-principles calculation and experiments. Alloying Sb on Bi site and Se on Te site induce charged structural defects, leading to a significant change in the carrier concentration. For Bi_2–x Sb_xTe_2.994Cl_0.006 compounds, alloying Sb on Bi site reduces the formation energy of the \mathrmS\textb_\mathrmTe__2 antisite defect, which generates the antisite defect \mathrmS\textb_\mathrmTe__2 and accompanied with the increase of the minority carrier concentration from 2.09×10¹⁶ to 3.99×10¹⁷ cm^–3. The increase of the minority carrier severely deteriorates the electrical transport properties. In contrast, alloying Se in the Bi_1.8Sb_0.2Te_2.994–ySe_yCl_0.006 compound significantly lowers the formation energy of the complex defect \mathrmS\mathrme_\mathrmTe+\mathrmS\mathrmb_\mathrmBi, which becomes more energetically favorable and suppresses the formation of the antisite defect \mathrmS\textb_\mathrmTe__2. As a result, the concentration of minority carriers decreases to 1.46×10¹⁶ cm^–3. This eliminates the deterioration effect of the minority carrier on the electrical transport properties of the material and greatly improves the power factor. A maximum power factor of 4.49 mW/(m·K²) is achieved for Bi_1.8Sb_0.2Te_2.944Se_0.05Cl_0.006 compound at room temperature. By reducing thermal conductivity through intensifying the phonon scattering via alloying Sb and Se, the maximum ZT value of 0.98 is attained for Bi_1.8Sb_0.2Te_2.844Se_0.15Cl_0.006 compound at room temperature. Our finding provides an important guidance for adjusting point defects, carrier concentrations, and thermoelectric performances in Bi₂Te₃-based compounds with complex compositions.