The performance of a novel two-stage indirect/thermoelectric assisted direct evaporative cooling (i.e. IEC/TDEC) system is studied by using experimental and numerical simulation methods. In the IEC/TDEC system, the outdoor air is firstly pre-cooled in the first stage cross-flow regenerative IEC to make full use of the nature cooling source, and then further cools down in the second stage TDEC. An experimental set up is designed and built to investigate the influences of main operation parameters (i.e. operating current and number of TEC modules, inlet temperature, humidity and velocity of primary air, the mass flow rate ratio of regenerative air to primary air in the IEC, and also the mass flow rate of cooling water in the TDEC) on the system performance. It is found that the outlet air temperature and relative humidity could be conditioned to meet the comfort demand by adjusting the influential operating parameters. The dew point efficiency could be higher than unity, and the air moisture content increases or decreases dependent on given working conditions. The numerical model of the IEC/TDEC system is established, and validated by comparing with experimental results. The numerical results agree well with experimental results with relative errors within ±10%. Then, the working parameters of TEC modules and several mass flow rate allocation ratios of air are optimized theoretically by using the numerical model. Analytical results show that in the premise of a certain dew point efficiency, a maximum coefficient of performance can be obtained by adjusting the operating current and number of TEC modules. Moreover, the inlet velocity of primary air and two main mass flow rate allocation ratios of air can be optimized to achieve higher system performance.