The cooling heat transfer and pressure drop of supercritical CO2 in horizontal wavy microchannels were numerically investigated. With the aim to provide a reference for gas cooler optimization design in trans-critical CO2 applications. Inlet mass flux ranging from 127.1 to 400 kg m−2 s−1, inlet temperature ranging from 310 to 325 K and inlet pressure ranging from 7 to 9 MPa were defined at the channel inlet. Uniform wall heat flux ranged from 9 to 40 kW m−2. Simulations started with the verification of nine turbulence models compared with the experimental data, and a relatively better prediction was achieved by Lam and Bremhorst model. The predictive accuracy of numerical results was assessed by comparing heat transfer coefficient and pressure drop with experimental data and empirical correlations in literatures. After the validation, the effects of the operating conditions on both heat transfer coefficient and pressure drop were analyzed in detail. The wavy microchannels showed a significant edge in heat transfer performance, while a slight increase in pressure drop compared with the straight ones. Furthermore, the significant buoyancy effect gave a complementary explanation to the mechanism of effects of operating conditions on the heat transfer coefficient.