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In this paper, a combined numerical and experimental approach for the estimation of the average friction factor along adiabatic microchannels with compressible gas flows is presented. Pressure-drop experiments are performed for a rectangular microchannel with a hydraulic diameter of 295 μ m by varying Reynolds number up to 17,000. In parallel, the calculation of friction factor has been repeated numerically and results are compared with the experimental work. The validated numerical model was also used to gain an insight of flow physics by varying the aspect ratio and hydraulic diameter of rectangular microchannels with respect to the channel tested experimentally. This was done with an aim of verifying the role of minor loss coefficients for the estimation of the average friction factor. To have laminar, transitional, and turbulent regimes captured, numerical analysis has been performed by varying Reynolds number from 200 to 20,000. Comparison of numerically and experimentally calculated gas flow characteristics has shown that adiabatic wall treatment (Fanno flow) results in better agreement of average friction factor values with conventional theory than the isothermal treatment of gas along the microchannel. The use of a constant value for minor loss coefficients available in the literature is not recommended for microflows as they change from one assembly to the other and their accurate estimation for compressible flows requires a coupling of numerical analysis with experimental data reduction. Results presented in this work demonstrate how an adiabatic wall treatment along the length of the channel coupled with the assumption of an isentropic flow from manifold to microchannel inlet results in a self-sustained experimental data reduction method for the accurate estimation of friction factor values even in presence of significant compressibility effects. Results also demonstrate that both the assumption of perfect expansion and consequently wrong estimation of average temperature between inlet and outlet of a microchannel can be responsible for an apparent increase in experimental average friction factor in choked flow regime.