The objective of this study was to engineer a biodegradable polymeric system for sustained release of piperine for cancer treatment. We prepared nanofibrous patches of poly(e-caprolactone) (PCL) and gelatin (GEL) blends of different ratios by electrospinning. The PCL/GEL nanofibers were loaded with up to 30 wt % piperine, a phytochemical derived from black pepper, which is believed to exhibit anticancer, antiarthritis, antibacterial, antioxidant, and anti-inflammatory properties. Scanning electron microscopy revealed that the fiber diameter was in the range of 300-400 nm. Fourier-transform infrared spectroscopy confirmed that the drug was successfully loaded into the nanofiber mats. In vitro release kinetics revealed the sustained release of the drug with SO% release in 3 days from the PCL/GEL (50:50 by weight) blend fibers. The reduced viability and growth of HeLa and MCF-7 cancer cells on the piperine eluting nanofibers demonstrated anticancer activity in vitro. The proliferation of noncancerous cells such as NIH3T3 cells and human mesenchymal stem cells was affected to a markedly lesser extent. Flow cytometry revealed that the released piperine induced the generation of reactive oxygen species (ROS) and cell cycle arrest in the G2/M phase, leading to cell death of cancer cells. The findings of this study suggest that piperine-loaded nanofiber mats could be developed into implantable biodegradable patches for use in postsurgical cancer treatment.