Bi ₂Te ₃-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 Bi ₂Te ₃-based alloy. Herein, a series of Cl doped n-type quaternary Bi _2–xSb _xTe _3–ySe _ycompounds 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–xSb _xTe _2.994Cl _0.006compounds, alloying Sb on Bi site reduces the formation energy of the ${\mathrm{S}}{{\text{b}}_{{\mathrm{Te}}}}_{_2}$ antisite defect, which generates the antisite defect ${\mathrm{S}}{{\text{b}}_{{\mathrm{Te}}}}_{_2}$ and accompanied with the increase of the minority carrier concentration from 2.09×10 ¹⁶to 3.99×10 ¹⁷cm ^–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 _0.006compound significantly lowers the formation energy of the complex defect ${\mathrm{S}}{{\mathrm{e}}_{{\mathrm{Te}}}}$ + ${\mathrm{S}}{{\mathrm{b}}_{{\mathrm{Bi}}}}$ , which becomes more energetically favorable and suppresses the formation of the antisite defect ${\mathrm{S}}{{\text{b}}_{{\mathrm{Te}}}}_{_2}$ . As a result, the concentration of minority carriers decreases to 1.46×10 ¹⁶cm ^–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·K ²) is achieved for Bi _1.8Sb _0.2Te _2.944Se _0.05Cl _0.006compound at room temperature. By reducing thermal conductivity through intensifying the phonon scattering via alloying Sb and Se, the maximum ZTvalue of 0.98 is attained for Bi _1.8Sb _0.2Te _2.844Se _0.15Cl _0.006compound at room temperature. Our finding provides an important guidance for adjusting point defects, carrier concentrations, and thermoelectric performances in Bi ₂Te ₃-based compounds with complex compositions.