A Quality by Design approach was taken to assess the influence of several formulation parameters on critical quality attributes of liquisolid pellets (LPs) obtained by extrusion-spheronization. Two mixture experimental designs were used, one for each of the non-volatile solvents (NVS) studied: Kolliphor® EL or PEG 400. The studied parameters were the concentrations of NVS (A-Kolliphor® EL, 0–40% w/w; or PEG 400, 0–31.1% w/w), coating material (B-crospovidone, 0–50.3% w/w) and carrier (C-microcrystalline cellulose, MCC, 27–100% w/w). The critical quality attributes assessed were amount of granulation liquid required for extrusion/spheronization, residual moisture, particle size, particle size distribution, bulk density, tapped density, true density, Carr's Index, Hausner Ratio, aspect ratio, angle of repose and friability. All hierarchical terms and interactions were evaluated to determine the statistical relevance of each term. Mathematical models were determined by linear regression, taking into account statistically relevant terms. Lack of Fit, R2, adjusted R2 and adequate precision were assessed to determine the fitness of each mathematical model. It was possible to identify and understand parameters affecting critical quality attributes of LPs, as well as the magnitude of these effects. The mathematical models developed were robust and can be used to predict optimal LPs excipient compositions within the experimental domains assessed. This study provides an overall understanding of the impact of excipients on quality attributes of blank LPs, a critical knowledge to the implementation of this novel application of liquisolid systems.