In spite of wide applications of powders in industry, there is a lack of sufficient knowledge regarding the mixing of poly-disperse particles in rotary drum and slant cone mixers. The main objective of this study was to explore the mixing quality of mono-disperse, bi-disperse, tri-disperse, and poly-disperse particles inside rotary drum and slant cone mixers as a function of the drum speed, particle size, agitator speed, and the initial loading method through the discrete element method (DEM). To achieve this objective, experimental work and simulations were carried out. DEM results were validated using experimental data obtained from both sampling and image analysis techniques. DEM simulation results were in good agreement with the experimentally determined data, both qualitatively and quantitatively. Three major loading methods were defined: side-side, top-bottom, and back-front. Also, the mixing metric was utilized to measure the mixing quality. For bi-disperse particles inside the slant cone mixer, the mixing index increased to a maximum and decreased slightly before reaching a plateau at the drum speed of 15 rpm with different loading methods as a direct result of the segregation of particles of different sizes. The same behavior was observed in the rotary drum for bi-disperse, tri-disperse, and poly-disperse particles. The effect of agitator speed on the mixing performance for bi-disperse particles inside the slant cone mixer was also investigated. The addition of the agitator increased the mixing quality and reduced the segregation of particles with different sizes. The best mixing qualities for the tri-disperse and poly-disperse particles inside the rotary drum were recorded for the top-bottom smaller-to-larger loading method. For the slant cone mixer, highest mixing indices for tri-disperse and poly-disperse particles with the top-bottom smaller-to-larger loading method were obtained at drum speeds of 15 and 55 rpm, respectively. The impact of segregation for both mixers was reduced by introducing additional intermediate size particles.