The difference between free energy changes occurring at two chemical states can be rigorously estimated via alchemical free energy (AFE) simulations. Traditionally, most AFE simulations are carried out under the classical energy potential treatment; then, accuracy and applicability of AFE simulations are limited. In the present work, we integrate a recent second-order generalized ensemble strategy, the orthogonal space random walk (OSRW) method, into the combined quantum mechanical/molecular mechanical (QM/MM) potential based AFE simulation scheme. Thereby, within a commonly affordable simulation length, accurate QM/MM alchemical free energy simulations can be achieved. As revealed by the model study on the equilibrium of a tautomerization process of hydrated 3-hydroxypyrazole and by the model calculations of the redox potentials of two flavin derivatives, lumichrome (LC) and riboflavin (RF) in aqueous solution, the present OSRW-based scheme could be a viable path toward the realization of practically efficient QM/MM AFE simulations.