The impact of hot-melt extrusion (HME) on the solid-state properties of four methacrylic (Eudragit® L100-55, Eudragit® EPO, Eudragit® RSPO, Eudragit® RLPO) and four polyvinyl (Kollidon® VA64, Kollicoat® IR, Kollidon® SR, and Soluplus®) polymers was studied. Overall, HME decreased Tg but increased electrostatic charge and surface free energy. Packing density decreased with electrostatic charge, whereas Carr’s and Hausner indices showed a peak curve dependency. Overall, HME reduced work of compaction (Wc), deformability (expressed as Heckel PY and Kawakita 1/b model parameters and as slope S′ of derivative force/displacement curve), and tablet strength (TS) but increased elastic recovery (ER). TS showed a better correlation with S′ than PY and 1/b. Principal component analysis (PCA) organized the data of neat and extruded polymers into three principal components explaining 72.45% of the variance. The first included Wc, S′ and TS with positive loadings expressing compaction, and ER with negative loading opposing compaction; the second included PY, 1/b, and surface free energy expressing interactivity with positive loadings opposing tap density or close packing. Hierarchical cluster analysis (HCA) assembled polymers of similar solid-state properties regardless of HME treatment into a major cluster with rescaled distance Cluster Combine Index (CCI) < 5 and several other weaker clusters. Polymers in the major cluster were: neat and extruded Eudragit® RSPO, Kollicoat® IR, Kollidon® SR, Soluplus®, and extruded Eudragit® L100-55. It is suggested that PCA may be used to distinguish variables having similar or dissimilar activity, whereas HCA can be used to cluster polymers based on solid-state properties and pick exchangeable ones (e.g., for sustain release or dissolution improvement) when the need arises.