To develop a highland barley-based whole-grain biscuit with improved palatability and functional benefits for dyspepsia that embodies the concept of medicinal-food homology, solid-state fermented highland barley whole-grain powder (processed with Lactobacillus acidophilus) was used as a primary ingredient, and rheological and thermal properties of the dough, as well as texture and sensory scores of the biscuit, were measured. Response surface methodology (RSM) was used to optimize the formula of the biscuits. After the addition of HMSC, powdered sugar, and NaHCO3, dough elasticity (G') and viscosity (G") increased with the increase in frequency, and viscosity decreased with the increase in shear rate. With the increase in the mass fractions of powdered sugar and NaHCO3, the gelatinization temperature increased, and the enthalpy change decreased. After the addition of HMSC, the hardness of biscuits first decreased and then increased, whereas viscosity and chewiness significantly increased (P<0.05). After the addition of powdered sugar and NaHCO3, the hardness, brittleness, viscosity, and chewiness of the biscuits significantly decreased (P<0.05), whereas the samples treated with NaHCO3 exhibited increased chewiness. RSM results showed that mass fractions of 7.7%, 11.3%, and 0.64% for HMSC, powdered sugar, and sodium bicarbonate, respectively, yielded the highest sensory score for the biscuits. A crispy biscuit with digestive-enhancing effects was successfully developed, providing novel insights for the development of homology-of-medicine-and-food products and whole-grain foods.