Sorghum (Sorghum bicolor) is a dietary staple for over 500 million people in the world.  It has the potential to alleviate negative health effects of obesity, diabetes, cancer, cardiovascular disease, and other inflammatory diseases. Many varieties are rich in polyphenols, secondary plant metabolites that have anti-inflammatory properties, but few studies have investigated the anti-inflammatory potential of natural genetic variation in sorghum polyphenols.  Methods and results: (1) To survey the natural variation of sorghum polyphenols, we measured concentration of total polyphenols, anthocyanins, and condensed tannins in 376 worldwide sorghum accessions using near infrared spectroscopy (NIRS); (2) To identify candidate genes responsible for the variation in concentration of condensed tannins, we sequenced the sorghum accessions using genotyping by sequencing (GBS), and then conducted a genome wide association study (GWAS) using the NIR measurements and the GBS data; and (3) To evaluate anti-inflammatory effects of sorghum polyphenols, we treated ANA-1 mouse macrophage cells with sorghum polyphenol extracts, and then stimulated the cells with interferon gamma to produce an inflammatory response. The pro-inflammatory proteins iNOS and COX-2 were measured by Western blot analysis. Conclusions: There is a great deal of natural variation in sorghum polyphenols.  More work should be done on the genetic variation of polyphenols in sorghum and their role as anti-inflammatory compounds.