Agent-based models (ABMs) provide a flexible multilayer platform for incorporating various modeling techniques into a single hybrid model for designing optimal biomaterial scaffolds for angiogenesis in tissue engineering applications. Scaffold geometrical variables are considered as design variables. The growth-factor concentration profile is the only process variable considered in this study. The product variables used to illustrate the combined effects of scaffold design variables and process variables on the outcome of angiogenesis include the density and depth of capillary invasion within the scaffold. The scaffold design process and the ABM developed to simulate angiogenesis are described in this article. The performance of the ABM and the vascularization of the polymer scaffolds are evaluated by simulation studies. The effects of pore size, pore size distribution, and interconnectivity on the total blood vessel length, invasion depth, and total number of sprouts formed during the vascularization process are reported. The integration of the simulation of angiogenesis with ABMs and scaffold design techniques provides an iterative process for designing optimal scaffold structures. Such an approach facilitates faster design of optimized scaffolds with significantly less cost and enables better understanding of the mechanisms of angiogenesis of polymer scaffolds for tissue engineering applications.