Sorghum (Sorghum bicolor) is an ancient grain and the fifth most produced cereal worldwide, and the most consumed cereal in the semi-arid regions of Africa and Asia, being a key grain for the diet of about 500 million people. It is rich in phenolic compounds (like flavonoids, 3-deoxyanthocyanidins, phenolic acids), resistant starch, and dietary fiber, which may beneficially influence intestinal health. This systematic review analyzed 22 in vivo studies to assess the effects of sorghum processing on bioactive compounds and their effects on intestinal health. Evidence suggests that sorghum modulates microbiota composition, enhances epithelial barrier integrity, improves intestinal morphology, and alters short-chain fatty acid production. These benefits appear to be influenced by sorghum genotype, grain fraction, and processing method, like refinement, extrusion, and fermentation, which affect the bioavailability of phenolics. Some studies indicated the effects of sorghum phenolics on anti-inflammatory and improved tight junction protein expression. Additionally, we emphasized the lack of complete information in several studies by not specifying genotypes, varieties, processing, and profiles of bioactive compounds of the sorghums used, hindering the understanding of the mechanisms involved in improving intestinal health. Overall, this review supports the potential of sorghum as functional food and ingredient for intestinal health promotion.