ASYMMETRIC LEAVES 1 (AS1) is a MYB-type transcription repressor that controls leaf development by regulating KNOX gene expression, but the underlying molecular mechanism is still unclear. In this study, we demonstrated that AS1 can interact with the histone deacetylase HDA6 in vitro and in vivo. The KNOX genes were up-regulated and hyperacetylated in the hda6 mutant, axe1-5, indicating that HDA6 may regulate KNOX expression through histone deacetylation. Compared with the single mutants, the as1-1/axe1-5 and as2-1/axe1-5 double mutants displayed more severe serrated leaf and short petiole phenotypes. In addition, the frequencies of leaf lobes and leaflet-like structures were also increased in as1-1/axe1-5 and as2-1/axe1-5 double mutants, suggesting that HDA6 acts together with AS1 and AS2 in regulating leaf development. Chromatin immunoprecipitation assays revealed that HDA6 and AS1 bound directly to KNAT1, KNAT2, and KNATM chromatin. Taken together, these data indicate that HDA6 is a part of the AS1 repressor complex to regulate the KNOX expression in leaf development.