This paper presents the results of a combined experimental and analytical study of blended FDA-approved polymers [polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL)] with the potential for sustained localized cancer drug release. Porous drug-loaded 3D degradable PLGA-PEG and PLGA-PCL scaffolds were fabricated using a multistage process that involved solvent casting and particulate leaching with lyophilization. The physicochemical properties including the mechanical, thermal and biostructural properties of the drug-loaded microporous scaffolds were characterized. The release of the encapsulated prodigiosin (PG) or paclitaxel (PTX) drug (from the drug-loaded polymer scaffolds) was also studied experimentally at human body temperature (37 °C) and hyperthermic temperatures (41 and 44 °C). These characteristic controlled and localized in vitro drug release from the properties of the microporous scaffold were analyzed using kinetics and thermodynamic models. Subsequently, normal breast cells (MCF-10A) were cultured for a 28-day period on the resulting 3D porous scaffolds in an effort to study the possible regrowth of normal breast tissue, following drug release. The effects of localized cancer drug release on breast cancer cells and normal breast cell proliferation are demonstrated for scenarios that are relevant to palliative breast tumor surgery for 16 weeks under in vivo conditions. Results from the in vitro drug release show a sustained anomalous (non-Fickian) drug release that best fits the Korsmeyer-Peppas (KP) kinetic model with a non-spontaneous thermodynamic process that leads to a massive decrease in breast cancer cell (MDA-MB-231) viability. Our findings from the animal suggest that localized drug release from drug-based 3D resorbable porous scaffolds can be used to eliminate/treat local recurred triple negative breast tumors and promote normal breast tissue regeneration after surgical resection.