Sorghum is key for global food security due to its genetic variability, resilience, and rich phytonutrient content, which are linked to numerous health benefits. A systematic review assessed the health effects of sorghum by analyzing cell (n = 22), animal (n = 20), and human (n = 7) studies across antioxidant, anti-inflammatory, obesity, cancer, cardiovascular, and diabetes outcomes. This review, involving 42 papers and 177 researchers from 12 countries, collected data from sorghum accessions (acc) and significant effects. Studies used 68 identified and 8 unidentified sorghums, 57% red (n = 20), brown (n = 5), and black (n = 17) pericarp colors, and evaluated whole (n = 31), brans (n = 11), and decorticated grains (n = 2). Colored sorghum, richer in phenolic compounds, especially 3-deoxyanthocyanins and tannins, inhibited cancer cell activities, including proliferation, tumor growth, and ROS activity, and promoted cell cycle arrest and apoptosis. Sorghum elevated HO1 and eNOS expression for cardiovascular, health-reduced platelet aggregation, and modulated platelet microparticles. They also suppressed inflammation markers and decreased lipid accumulation. Animal studies indicated sorghum's potential across antioxidant capacity, cancer and inflammation mitigation, and lipid and glucose metabolism. Translating these findings to human scenarios requires caution, especially considering cell studies do not fully represent polyphenol metabolism. Human studies provided mixed results, indicating antioxidant and potential anti-inflammatory benefits and nuanced effects on glucose and lipid metabolism. The main risks of bias highlighted challenges in quantifying phytonutrients, identifying sorghum acc features, and lack of assessors blinding. Nonetheless, sorghum emerges as a promising functional food for countering chronic diseases in Western diets.