Based on the first-principles calculation and Boltzmann transport equation, a new Bi2Te3-based material with excellent thermoelectric properties, namely monolayer BiSbTeSe2, is predicted. By systematically calculating the electronic band structure and thermoelectric transport properties of monolayer BiSbTeSe2, it is found that the maximum Seebeck coefficient of monolayer BiSbTeSe2 reaches the highest value (522 μV·K-1) at 300 K, and the maximum ratio of power factor to relaxation time at 500 K is 5.78 W·m-1·K-2·s-1. In addition, the monolayer BiSbTeSe2 has lower lattice thermal conductivity and higher mobility. Under the optimum p-type doping, the thermoelectric figure of merit ZT of monolayer BiSbTeSe2 at 500 K is as high as 3.95. The excellent performance of monolayer BiSbTeSe2 shows that it has potential application value in the field of medium-temperature electrical devices in the temperature range of 300~500 K, which can provide design basis for further developing high-performance Bi2Te3-based thermoelectric materials.