Diseases of the esophagus affect its function and often lead to replacement of long sections of the organ. Current healing methods involve the use of bioscaffolds processed from other animal models. Although the properties of these animal models are not exactly the same as those of the human esophagus, they nevertheless present a reasonable means of assessing the biomechanical properties of the esophageal tissue. Besides, sheep bear many similarities physiologically to humans and they also suffer from same diseases as humans. The morphology of their esophagus is also comparable to that of humans. Thus, in the study, an ovine esophagus was studied. Studies on the planar biaxial tests of the gross esophageal anatomy are limited. The composite nature of the gross anatomy of the esophagus makes the application of structure-based models such as Holzapfel-type models very difficult. In current studies the tissue is therefore often separated into specific layers with substantial collagen content. The effects of adipose tissue and other non-collagenous tissue often make the mechanical behavior of the esophagus widely diverse and unpredictable using deterministic structure-based models. Thus, it may be very difficult to predict its mechanical behavior. In the study, an NARX neural network was used to predict the stress–strain response of the gross anatomy of the ovine esophagus. The results show that the NARX model was able to achieve a correlation above 99.9% within a fitting error margin of 16%. Therefore, the use of artificial neural networks may provide a more accurate way of predicting the biaxial stress–strain response of the esophageal tissue, and lead to further improvements in the design and development of synthetic replacement materials for esophageal tissue.