To ensure food security in Africa and Asia, developing sorghum varieties with grain quality that matches consumer demand is a major breeding objective that requires a better understanding of the genetic control of grain quality traits. The objective of this targeted association study was to assess whether the polymorphism detected in six genes involved in synthesis pathways of starch (Sh2, Bt2, SssI, Ae1, and Wx) or grain storage proteins (O2) could explain the phenotypic variability of six grain quality traits [amylose content (AM), protein content (PR), lipid content (LI), hardness (HD), endosperm texture (ET), peak gelatinization temperature (PGT)], two yield component traits [thousand grain weight (TGW) and number of grains per panicle (NBG)], and yield itself (YLD). We used a core collection of 195 accessions which had been previously phenotyped and for which polymorphic sites had been identified in sequenced segments of the six genes. The associations between gene polymorphism and phenotypic traits were analyzed with Tassel. The percentages of admixture of each accession, estimated using 60 RFLP probes, were used as cofactors in the analyses, decreasing the proportion of false-positive tests (70%) due to population structure. The significant associations observed matched generally well the role of the enzymes encoded by the genes known to determine starch amount or type. Sh2, Bt2, Ae1, and Wx were associated with TGW. SssI and Ae1 were associated with PGT, a trait influenced by amylopectin amount. Sh2 was associated with AM while Wx was not, possibly because of the absence of waxy accessions in our collection. O2 and Wx were associated with HD and ET. No association was found between O2 and PR. These results were consistent with QTL or association data in sorghum and in orthologous zones of maize. This study represents the first targeted association mapping study for grain quality in sorghum and paves the way for marker-aided selection.