Recently, much attention has been paid to the direct use of acetone-n-butanol-ethanol (ABE) as a biofuel. However, the skeletal mechanism of ABE for engine applications was rarely reported. Therefore, a skeletal mechanism to predict the combustion and emission characteristics of diesel-ABE blends in engines was developed in this study. A reduced mechanism considering the oxidation of acetone, n-butanol, and ethanol was first established on the basis of the methods of directed relation graph with error propagation and sensitivity analysis, computational singular perturbation, and reaction pathway analysis. It was then combined with a reduced n-heptane/toluene mechanism with soot formation mechanism embedded and a reduced NOx formation mechanism. After optimizing the reaction rate constants of the key reactions in the coupled mechanism, the skeletal mechanism of n-heptane/toluene-acetone-n-butanol-ethanol (referred as HT-ABE) consisting of 127 species and 507 reactions was finally generated and validated against ignition delay times, premixed flame species profiles, and three-dimensional (3D) engine simulations. The results show that the combustion and emission characteristics of diesel-ABE blends are well reproduced by the current mechanism. It is indicated that the newly developed HT-ABE mechanism can be applied to simulate practical ABE combustion in a diesel engine.