Ischemic heart diseases, such as coronary artery disease and microvascular disease, are cardiovascular pathologies that cause reduced blood supply to the heart muscle. Acute and chronic ischemia cause cardiomyocytes to die, and these cells are not naturally replaced as part of the wound healing process in the heart. To promote neovascularization in the wound bed and in implanted engineered tissues, we have developed a collagen-alginate microspheres scaffold intended for local release of drugs and growth factors in order to recruit host endothelial cells to the area and provide them with geometrical cues to form new vessels. Optimization of alginate microspheres included modulation of nitrogen pressure, alginate and CaCl2 concentrations, nozzle size, and velocity of extrusion to achieve monodisperse populations of 100 μm diameter microspheres with protein release over 3 days. In vitro incorporation of fibroblasts in the bulk collagen demonstrated cellular compatibility with embedded alginate microspheres. An in vitro vessel formation assay, performed with human umbilical vein endothelial cells (HUVECs) immobilized in the collagen phase of the collagen-alginate microspheres scaffolds, showed that HUVECs formed networks following the 3-dimensional pattern of the microspheres even in the absence of growth factor. Implantation of acellular collagen-alginate microspheres scaffolds onto healthy rat hearts confirmed the invasion of host cells at one week. Together, these results suggest that the collagen-alginate microspheres scaffold is a viable, tunable therapeutic approach for directing neovascularization in engineered tissues and in the heart after ischemic events.