The esophagus, like other soft tissues, exhibits nonlinear and anisotropic mechanical properties. As a composite structure, the properties of the outer muscle and inner mucosal layer are different. It is expected that the complex mechanical properties will induce nonhomogeneous stress distributions in the wall and nonuniform tissue remodeling. Both are important factors which influence the function of mechanosensitive receptor located in various layers of the wall. Hence, the characterization of the mechanical properties is essential to understand the neuromuscular motion of the esophagus. In this study, the uniaxial tensile tests were conducted along two mutually orthogonal directions of porcine esophageal tissue to identify the directional (circumferential and axial), regional (abdominal, thoracic, and cervical), and layer (muscle and mucosa) variations of the mechanical properties. A structure-based constitutive model, which took the architectures of the tissue’s microstructures into account, was applied to describe the mechanical behavior of the esophagus. Results showed that the constitutive model successfully described the mechanical behavior and provided robust estimates of the material parameters. In conclusion, the model was demonstrated to be a good descriptor of the mechanical properties of the esophagus and it was able to facilitate the directional, layer, and regional comparisons of the mechanical properties in terms of the associated material parameters.