Different types of ethylcellulose-based mini-matrices were prepared by hot-melt extrusion and thoroughly characterized in vitro. Metoprolol tartrate was used as model drug, and various amounts and types of polyethylene glycol (PEG)/polyethylene oxide (PEO) were added as release rate modifiers. Based on the experimental results, appropriate mathematical theories were identified/developed, allowing for a better understanding of the underlying drug release mechanisms. For instance, it could be shown that at high initial PEG/PEO contents and/or intermediate initial PEG/PEO contents of low molecular weight, drug diffusion with time- and position-independent diffusivities is predominant. In contrast, at low initial PEG/PEO contents and intermediate initial PEG/PEO contents of high molecular weight, the time- and position-dependent dynamic changes in the matrix porosities significantly affect the conditions for drug and PEG/PEO diffusion. These dynamic changes must be taken into account in the mathematical model. Importantly, the proposed theories are mechanistic realistic and also allow for the quantitative prediction of the effects of the device design on the resulting drug release patterns. Interestingly, these quantitative predictions could be confirmed by independent experiments. Furthermore, Raman spectroscopy allowed for the determination of the resulting drug concentration-position profiles within the mini-matrices as a function of time and confirmed the theoretical predictions.