This paper numerically studies the Mach number effect on cruise performance of a Co-Flow Jet (CFJ) general aviation (GA) airplane at freestream Mach number of 0.15, 0.30, and 0.46 with an aspect ratio of 21.3. An optimized CFJ-NACA-6421 airfoil is used for the CFJ wing. The advantages of using a thick airfoil are two folds: 1) higher cruise lift coefficient; 2) lighter weight. The numerical simulations employ the intensively validated in house FASIP CFD code, which utilizes a 3D RANS solver with Spalart-Allmaras (S-A) turbulence model, 3rd order WENO scheme for the inviscid fluxes, and 2nd order central differencing for the viscous terms. Two constant Cµ of 0.03 and 0.04 are studied to examine the effect on the aircraft cruise performance. The angle of attack (AoA) is held at 5◦ corresponding to the optimal aerodynamic and productivity efficiency in the previous study for the wing performance at different Mach number. At Cµ of 0.03, the flow is very well attached for Mach 0.15, which gives the highest pure lift to drag ratio CL /CD, the corrected aerodynamic efficiency with CFJ power coefficient included (CL /CD )c, and the productivity efficiency (CL2/CD)c . When the Mach number is increased to 0.46, the lift coefficient is increased by 8.6% from 1.16 to 1.26 due to the compressibility effect, but all the three aerodynamic performance parameters, CL /CD, (CL /CD )c, and (CL2/CD)c drop substantially. The reason is that the a flow separation at the wing-fuselage junction occurs. The drag coefficient is significantly increased by 67% when the Mach number is increased form 0.15 to 0.46 due to the flow separation, higher skin friction drag, and higher induced drag. When the Cµ is increased to 0.04, the wing-fuselage junction flow separation is removed. The CFJ power coefficient is increased by 33%, but remains at a very low level due to the low energy expenditure feature of the CFJ flow control. The CL /CD, (CL /CD )c, and (CL2/CD)c are significantly increased by 21.3%, 10.7%, and 19.8% respectively. In other words, the CFJ power increased due to Cµ of 0.04 at Mach 0.46 is converted to more system efficiency gain reflected by enhanced (CL /CD )c and (CL2/CD)c, which include the CFJ power coefficient. The system efficiency gains are attributed to the increased CL and substantially reduced CD due to the removed flow separation at low CFJ energy expenditure.