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Proso millet (<i>Panicum miliaceum</i>) contains about 12% protein with kaifirins being the major storage protein. Despite having numerous nutritional and agricultural advantages the crop has limited human consumption. In order to promote the edible uses of millet in US the protein digestibility was evaluated. De-hulled proso millet flour was subjected to wet heating (25-100°C) and oven heating (100°C) at various moisture contents (7%, 10%, 20% and 30%) and the pepsin digestibility was measured. It was found that heating the flour beyond 60°C with a moisture content above 10% resulted in reduction of digestibility from 80% to 35%. This trend was also apparent after sequential modelling of both gastric (pepsin) and intestinal (pancreatin) digestion. Further investigation ruled out the formation of intramolecular disulfide linkages and interactions of proteins with starch, lipids, and phenolics as the major causes for lower digestibility after heating. On the other hand, heating the flour with urea prevented the loss in digestibility, suggesting hydrophobic interactions among millet proteins on heating as the driver for lower digestibility. Exploring effect of non-thermal processing techniques and other chaotrops on digestibility of millets could help in understanding and possibly rectifying the observed problem.