Sorghum was chosen as the model crop, because it is a heat-resilient, high biomass yielding, and a multipurpose feedstock (food, feed, fiber, bioenergy) suitable for the semi-arid regions. Stems and leaves harvested from a dryland grain sorghum variety were ground and pre-extracted with ethanol and water to remove monosaccharides, wax, proteins, and anthocyanins. The extractives-free biomass was then hydrothermally fractionated at the pre-determined conditions of 170 °C for 30 min, at 10% w/v solid loading, in a 2-liter Parr reactor, to remove the XOS-enriched product. The liquid hydrolysates were freeze-dried and then used to prepare the milk-replacement formula (18% crude protein, 3% crude fat, 8% crude fiber) for pre-weaned dairy calves. The control group was fed with a commercial source of crude fiber whereas the treatment group was fed with the sorghum-XOS product, from day 1 to 21. Based on the body weight gain, histopathology, and ex vivo inflammatory studies in the samples of jejunum, ileum, and colon tissues, we concluded that the crude-XOS extracts from sorghum provided similar benefits to that of the commercial source (i.e., inulin). Specifically, the sorghum XOS product protected the gut integrity and reduced the occurrence of inflammatory factors in hindgut epithelia by 23%. Overall, our study demonstrated the viability of crude XOS extracts from sorghum as a health promoting dietary supplement for dairy calves.