This paper implements Co-flow Jet (CFJ) active flow control (AFC) on the M2129 serpentine duct for mitigating flow separation with low energy consumption. Various locations and slot widths of CFJ suction duct are studied and the energy expenditure of each case is analyzed. The 3D Reynolds Averaged Navier-Stokes (RANS) equations with one-equation Spalart-Allmaras turbulence model is used. The experimental data of AGARD test case 3.1, which has throat Mach number of 0.79, is used for validation. The predicted total pressure recovery agrees very well with the experiment with the discrepancy of less than 1%. The distortion coefficient (DC60) is also in an acceptable agreement with the experiment. The simulation result is further validated using the wall static pressure distribution, which also achieves a good agreement with the experiment. For the CFJ S-duct, a horn shaped slot geometry is adopted for the CFJ injection and suction slots to minimize the separation caused by CFJ sides wall. For the optimum configuration of the CFJ S-duct, a small distortion coefficient of 1.7% is achieved with the averaged total pressure recovery increased by 1.9%. The optimum CFJ configuration is able to substantially reduce the required CFJ power consumption due to placing the suction at the geometric inflection point. Overall, the CFJ active flow control is demonstrated numerically to be very effective to mitigate the S-duct flow distortion and improve total pressure recovery.