Piezoelectric materials that generate electrical signals in response to mechanical strain can be used in tissue engineering to stimulate cell proliferation. Poly (vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)), a piezoelectric polymer, is widely used in biomaterial applications. We hypothesized that incorporation of zinc oxide (ZnO)nanoparticles into the P(VDF-TrFE) matrix could promote adhesion, migration, and proliferation of cells, as well as blood vessel formation (angiogenesis). In this study, we fabricated and comprehensively characterized a novel electrospun P(VDF-TrFE)/ZnO nanocomposite tissue engineering scaffold. We analyzed the morphological features of the polymeric matrix by scanning electron microscopy, and utilized Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry to examine changes in the crystalline phases of the copolymer due to addition of the nanoparticles. We detected no or minimal adverse effects of the biomaterials with regard to blood compatibility in vitro, biocompatibility, and cytotoxicity, indicating that P(VDF-TrFE)/ZnO nanocomposite scaffolds are suitable for tissue engineering applications. Interestingly, human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells cultured on the nanocomposite scaffolds exhibited higher cell viability, adhesion, and proliferation compared to cells cultured on tissue culture plates or neat P(VDF-TrFE) scaffolds. Nanocomposite scaffolds implanted into rats with or without hMSCs did not elicit immunological responses, as assessed by macroscopic analysis and histology. Importantly, nanocomposite scaffolds promoted angiogenesis, which was increased in scaffolds pre-seeded with hMSCs. Overall, our results highlight the potential of these novel P(VDF-TrFE)/ZnO nanocomposites for use in tissue engineering, due to their biocompatibility and ability to promote cell adhesion and angiogenesis.