Background: Sorghum is a cereal source of energy, carbohydrates, resistant starch, proanthocyanidins, and 3-deoxyanthocyanins; it promotes satiety by slowing digestion and benefits intestinal health. Objective: This study investigated the effects of extruded sorghum SC319 consumption on intestinal health, weight loss, and inflammatory markers in men with overweight. Methods: This was a randomized, controlled, single-blind clinical trial. Twenty-one men were randomly allocated into one of two groups: the sorghum group (test), which received 40 g of extruded SC319 whole sorghum (n = 10), or the wheat group (control), which received 38 g of extruded whole wheat (n = 11) for eight weeks. Results: The sorghum consumption increased the weight loss intragroup, decreased the body fat percentage intergroup, and did not change inflammatory markers, while the wheat group had increased IL-6 levels compared to baseline. Short-chain fatty acid production, fecal pH, and Alfa and Beta diversity indexes did not differ intra- and intergroup after interventions. However, sorghum consumption decreased genus levels of Clostridium_sensu_stricto 1, Dorea, and Odoribacter and increased CAG-873 and Turicibacter compared to baseline. Further, sorghum showed a tendency (p = 0.07) to decrease the proteobacteria phyla compared to wheat. Conclusion: Extruded sorghum SC319 improved intestinal microbiota and body composition and promoted weight loss, demonstrating its prebiotic potential.