A kinetic investigation was carried out in this work for an oxygenated fuel additive, 1,2-dimethoxyethane (1,2-DME) to reveal the oxidation chemistry responsible for its practical function as a cetane improver. Experiments were conducted for 1,2-DME/O2/N2 mixtures with different equivalence ratios (0.5, 1.0 and 2.0) in a high-pressure (10 atm) jet-stirred reactor (JSR) facility over the temperature range of 450–1100 K. Species concentration evolutions with the temperature were monitored with on-line Fourier transform infrared (FTIR) spectrometry and off-line gas chromatography (GC). The technique of photoionization molecular-beam mass spectrometry (PI-MBMS) was combined with another JSR setup operated at near-atmospheric pressure (700 Torr), for the purpose of probing reactive intermediates from 1,2-DME oxidation. A kinetic model was constructed based on the “reaction classes” strategy, which could satisfactorily predict speciation measurements in the current work. Pronounced low-temperature reactivity of 1,2-DME was observed under all investigated conditions, and crucial intermediates like ketohydroperoxides were detected with the PI-MBMS. Some specificities of 1,2-DME oxidation were elucidated through further model interpretations. The double ether groups imbedded in the fuel molecule make hydrogen abstractions easier and meanwhile hinder the chain-terminating concerted eliminations, so the low-temperature reactivity starts at relatively low temperatures (compared to n-hexane for example). Chain-branching reaction sequences following the second O2 additions proceed in the oxidizing mixtures, leading to the remarkable low-temperature reactivity of 1,2-DME which can be utilized as a cetane-improver.