The objective of the study was to select solid-state plasticizers for hot-melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer:plasticizer) and ternary (active pharmaceutical ingredient:polymer:plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin and Eudragit E PO were selected as model active pharmaceutical ingredient and polymer, respectively. Solubility parameters, thermal analysis, and rheological evaluation were used as assessment tools. Based on comparable solubility parameters, stearic acid, glyceryl behenate, and polyethylene glycol 8000 were selected as solid-state plasticizers. Binary and ternary physical mixtures were evaluated as a function of plasticizer concentration for thermal and rheological behavior. The thermal and rheological assessments also confirmed the miscibility predictions from solubility parameters. The understanding of thermal and rheological properties of the various mixtures helped in predicating plasticization efficiency of stearic acid, glyceryl behenate, and polyethylene glycol 8000. The evaluation also provided insight into the properties of the final product. An empirical model was also developed correlating rheological property of physical mixtures to actual HME process. Based on plasticizer efficiency, solid-state plasticizers and processing conditions can be selected for a HME process.