Resistance breeding is crucial for a sustainable control of wheat leaf rust and SNP-based genome-wide association studies (GWAS) are widely used to dissect leaf rust resistance. Unfortunately, GWAS based on SNPs explained often only a small proportion of the genetic variation. We compared SNP-based GWAS with a method based on functional haplotypes (FH) considering epistasis in a comprehensive hybrid wheat mapping population composed of 133 parents plus their 1,574 hybrids and characterized with 626,245 high-quality SNPs. In total, 2,408 and 1,139,828 significant associations were detected in the mapping population by using SNP-based and FH-GWAS, respectively. These associations mapped to 25 and 69 candidate regions, correspondingly. SNP-based GWAS highlighted two already-known resistance genes, i.e. Lr22a and Lr34-B, while FH-GWAS not only detected associations on these genes but also on two additional genes, i.e. Lr10 and Lr1. As revealed by a second hybrid wheat population for independent validation, using detected associations from SNP-based and FH-GWAS reached predictabilities of 11.72% and 22.86%, respectively. Therefore, FH-GWAS is not only more powerful to detect associations, but also improves the accuracy of marker-assisted selection as compared to the SNP-based approach.