Electrospun nanofibers have the potential to achieve high drug loading and the ability to sustain drug release. Mechanical properties of the drug-incorporated fibers suggest the-importance of drug polymer interactions. In this study, we investigated the mechanical properties of electrospun polycaprolactone (PCL) and poly (D,L-lactic-co-glycolic) acid (PLGA) fibers at various blend ratios in the presence and absence of a small molecule hydrophilic drug, tenofovir (TFV). Young's modulus of the blend fibers showed dependence on PLGA content and the addition of the drug. At a PCL/PLGA (20/80) composition, Young's modulus and tensile strength were independent of drug loading up to 40 wt% due to offsetting effects from drug polymer interactions. In vitro drug release studies suggested that release of TFV significantly decreased fiber mechanical properties. In addition, mechanically stretched fibers displayed a faster release rate as compared to the non-stretched fibers. Finally, drug partition in the blend fibers was estimated using a mechanical model and then experimentally confirmed with a composite of individually stacked fiber meshes. This work provides scientific understanding on the dependence of drug release and drug loading on the mechanical properties of drug-eluting fibers.