As a promising alternative biofuel, 2,5-dimethylfuran (DMF) has caused great concern recently. In this research, a new skeletal oxidation mechanism for DMF is built by merging the decoupling methodology with the reaction class-based global sensitivity analysis. First, the global sensitivity and path sensitivity analyses are used to identify the dominant reaction classes in the fuel-related submechanism of DMF. Then, the important isomers in the dominant reaction classes are chosen with the rate of production analysis. In addition, the vertical reaction lumping is performed to obtain global reactions for the reaction classes based on the steady-state assumption of the involved intermediate radicals. A skeletal C-4-C-6 submechanism is obtained. Based on the decoupling methodology, an original skeletal mechanism of DMF is constructed by adding the skeletal fuel-related sub-mechanism into a compact C-0-C-3 submechanism. Third, the reaction rate coefficients involving the fuel-related species are tuned within their uncertainty ranges through the genetic algorithm to ameliorate the predictions of the skeletal mechanism on autoignition times in shock tubes and key species evolution in jet-stirred reactors (JSRs). The final skeletal mechanism for DMF is obtained, consisting of 57 species and 212 reactions. The satisfactory agreement between the measurement and prediction shows that the final skeletal mechanism is able to well capture the ignition and combustion phenomenon of DMF under wide operating conditions.