Dimethyl ether (DME)/C1-C4 alkane mixtures are ideal fuel for homogeneous charge compression ignition (HCCI) engines. The comparison of ignition delay and multi-stage ignition for DME/C1-C4 alkane mixtures can provide theoretical guidance for expanding the load range and controlling the ignition time of DME HCCI engines. However, the interaction mechanism between DME and C1-C4 alkane under engine relevant high-pressure and low-temperature conditions remains to be revealed, especially the comprehensive comparison of the negative temperature coefficient (NTC) and multi-stage ignition characteristic. Therefore, the CHEMKIN-PRO software is used to calculate the ignition delay process of DME/C1-C4 alkane mixtures (50%/50%) at different compressed temperatures (600−2000 K), pressures (20−50 bar), and equivalence ratios (0.5−2.0) and the multi-stage ignition process of DME/C1-C4 alkane mixtures (50%/50%) over the temperature of 650 K, pressure of 20 bar, and equivalence ratio range of 0.3−0.5. The results show that the ignition delay of the mixtures exhibits a typical NTC characteristic, which is more prominent at a low equivalence ratio and pressure range. The initial temperature of DME/CH4 mixtures of the NTC region is the highest. In the NTC region, the ignition delay DME/CH4 mixtures are the shortest, whereas DME/C3H8 mixtures are the longest. At low-temperature and lean-burn conditions, DME/C1-C4 alkane mixtures exhibit a distinct three-stage ignition characteristic. The time corresponding to heat release rate and pressure peak is the shortest for DME/CH4 mixtures, and it is the longest for DME/C3H8 mixtures. Kinetic analysis indicates that small molecular alkane competes with the OH radical produced in the oxidation process of DME, which inhibits the oxidation of DME and promotes the oxidation of small molecular alkane. The concentration of active radicals and the OH radical production rate of elementary reactions are the highest for DME/CH4 mixtures, and they are the lowest for DME/C3H8 mixtures.