Numerical investigation on knock was conducted in a direct-injection diesel engine with port premixed dimethyl ether (DME) fuel. Knock combustion at various engine operating conditions with a fixed speed was simulated, and the effects of premixed DME ratio, injection timing, and exhaust gas recirculation (EGR) rate on knock suppression were studied based on the multidimensional computational fluid dynamics (CFD) analysis. A reduced diesel-DME kinetic mechanism coupled with the CFD model was used to obtain local pressure and radical concentration at various monitoring locations within the computation domain. A method with a band-pass filter was then employed to deal with pressure data, and maximum amplitude of pressure oscillation was adopted as an evaluation index of the knock intensity. The analysis of species concentration was also used to quantify knock here. The research results indicated the profiles of pressure and major intermediate species could provide useful information to quantify and predict knock for DME-diesel dual-fuel premixed compression-ignition combustion. Moreover, using EGR was an effective way to reduce the knock intensity and delay the knock onset. A lower DME premixed ratio and retarded injection timing could also mitigate the knock.