Strategies to increase rice productivity to meet the global demand have been the main concern of breeders around the world. Although a growing number of functional genes related to crop yield have been characterized, our understanding of its associated regulatory pathways is limited. Using rice as a model, we find that blocking miR396 greatly increases grain yield by modulating development of auxiliary branches and spikelets through direct induction of the growth regulating factor 6 (OsGRF6) gene. The upregulation of OsGRF6 results in the coordinated activation of several immediate downstream biological clades, including auxin (IAA) biosynthesis, auxin response factors, and branch and spikelet development-related transcription factors. This study describes a conserved microRNA (miRNA)-dependent regulatory module that integrates inflorescence development, auxin biosynthesis and signalling pathways, and could potentially be used in engineering high-yield crop plants.