Grain produced from cereal crops is a major source of human and animal feed worldwide. To understand the genetic basis of seed size variation, a component trait of grain yield, we conducted a genome-wide scan to detect evidence of selection in the Krug Yellow Dent long-term selection experiment for small and large seed size. The empirically estimated effective population size of the selected populations was 369 individuals, and previous reports demonstrated significant phenotypic divergence between the populations. Allele frequency estimates for 3,090,214 single nucleotide polymorphisms (SNPs) in the base population and selected populations were estimated from pooled whole genome resequencing of 48 individuals per population. Using FST values across sliding windows, 94 highly divergent regions were identified with a median of six genes per region. Additionally, 2,729 SNPs were identified that reached fixation in both selected populations with opposing fixed alleles, many of which clustered in two large regions of the genome. Copy number variation was also highly prevalent between the selected populations, with 532 total regions identified from coverage variation and comparative genome hybridization. Overlap between regions identified in the long-term selection experiment and nearly half of the regions identified from natural genetic variation for seed weight were observed. The results of this study provide insights into the genetic elements underlying seed size variation in maize and other cereal crops. In particular, genes underlying regions identified in this study support previous reports on the importance of rate of developmental and seed composition to seed size variation.