The introduction of high cetane components has enabled the use of low cetane base gasoline in compression ignition engines. This study provides an understanding of the autoignition characteristics of various ethers blended with light distillates. The spontaneous ignition of mixtures was herein studied both experimentally [ignition quality tester (IQT)] and computationally, allowing the impacts of distillate composition, ether structure, and reaction progress on key ignition pathways to be determined. Various multicomponent base fuel surrogates were formulated to closely match actual fuel composition, thereby accurately simulating the interplay between distillates and oxygenates. Despite its lower cetane number, di-n-butyl ether (DNBE) was found to promote a more vigorous ignition than diethylether. However, OH radical scavenging by p-xylene counteracts the DNBE effect. Two preignition phases may be distinguished, namely, oxidation initiation by ether and subsequent chemical runaway involving simultaneously fuel and ether. According to the present kinetic mechanism, direct cross-reactions between ether radicals and light distillate components have little impact on the ignition delay time under the IQT operating conditions. As ignition progress increases, ether contribution to OH production decreases and oxidation paths related to aliphatic and cyclic alkanes become dominant. In the case of polyoxymethylene methyl ethers, the extra production of formaldehyde during the ignition phase does not impair the overall reactivity. The respective effects of OME1 and OME3 on ignition may be explained by the emergence of a new OH production path from OME3 oxidation products, while methyl formate production from OME1 acts as an OH radical sink. Even though locally lean zones of the IQT reactor may favor specifically neopentane oxidation at the expense of n-hexane, the new OH production path remains active over a wide range of conditions. Overall, the present detailed model qualitatively captures the nonlinear impact of various ethers on autoignition over the 15–30 DCN range, which makes it attractive for optimizing low cetane fuel formulation.