Hybrid breeding facilitates the exploitation of heterosis and it can result in significant genetic gains and increased crop yields. Inefficient cross-pollination is a major limiting factor that hampers hybrid wheat seed production. In this study, we examined the genetic basis of anther extrusion (AE), which is an important trait in increasing cross-pollination, and thus improving seed set on the female lines and hybrid wheat seed production. We studied 300 segregating F2 plants and F2:3 families that result from a cross of two elite spring wheat lines. We observed that F2 and F2:3 populations hold significant and continuous genetic variation for AE, which suggests its reliable phenotypic selection. Composite interval mapping detected three quantitative trait loci (QTL) on chromosomes 3A, 5A, and 5D. The QTL on chromosome 5A (i.e., QAe.cimmyt-5A) was of large-effect, being consistently identified across generations, and spanned over 25 cM. Our study shows that (1) AE possesses strong genetic control (heritability), and (2) the QTL QAe.cimmyt-5A that imparted on an average of 20% of phenotypic variation can be used for marker-assisted selection (MAS) in breeding programs. In addition, pyramiding the large-effect QTL for MAS could efficiently complement the phenotypic selection since it is relatively easy and cheap to visually phenotype AE. This study reports the first large-effect QTL for AE in spring wheat, endorsing the use of this analysis in current hybrid wheat breeding and future Mendelization for the detection of underlying gene(s).