Despite advances in the development of degradable polymers for drug delivery, effective translation of drug-loaded materials is often hindered due to a poor understanding of matrix property combinations that promote controlled and sustained release. In this study, we investigated the influence of dominant factors on the release of a hydrophobic glucocorticoid dexamethasone (DEX) from electrospun meshes. Polycaprolactone meshes released 98% of the drug within 24 h, while poly(Llactide) meshes exhibited negligible release even after 28 days despite both polymers being slow-degrading. Differences in drugpolymer interactions and drug-polymer miscibility-but neither matrix degradation nor differences in bulk hydrophobicity- influenced DEX release from these semi-crystalline matrices. Poly(D,L-lactide-co-glycolide) 50:50 meshes possessing two different fiber diameters exhibited a sequential burst and sustained release, while poly(D,L-lactide-co-glycolide) 85:15 meshes cumulatively released 26% drug in a controlled manner. Although initial drug release from these matrices was driven by differences in matrix architecture and solid-state drug solubility, release toward the later stages was influenced by a combination of fiber swelling and matrix degradation as evidenced by gross and microstructural changes to the mesh network. We suggest that drug release from polymeric matrices can be better understood via investigation of critical matrix characteristics influencing release, as well as concomitant examination of drug-polymer interactions and miscibility. Our findings offer rational matrix design criteria to achieve controlled/extended drug release for promoting sustained biological responses. © 2020 American Chemical Society.