Sorghum and maize share a close evolutionary history that can be explored through comparative genomics1,2. To perform a large-scale comparison of the genomic variation between these two species, we analysed ~13 million variants identified from whole-genome resequencing of 499 sorghum lines together with 25 million variants previously identified in 1,218 maize lines. Deleterious mutations in both species were prevalent in pericentromeric regions, enriched in non-syntenic genes and present at low allele frequencies. A comparison of deleterious burden between sorghum and maize revealed that sorghum, in contrast to maize, departed from the domestication-cost hypothesis that predicts a higher deleterious burden among domesticates compared with wild lines. Additionally, sorghum and maize population genetic summary statistics were used to predict a gene deleterious index with an accuracy greater than 0.5. This research represents a key step towards understanding the evolutionary dynamics of deleterious variants in sorghum and provides a comparative genomics framework to start prioritizing these variants for removal through genome editing and breeding.