Plant lateral branches are important for plant architecture and plant production, but how plants determine their lateral branches remains to be further understood. Here we report that the CUC2/3-DA1-UBP15 regulatory module controls the initiation of axillary meristems, thereby determining the number of lateral branches in Arabidopsis. Mutation in the ubiquitin-dependent peptidase DA1 causes fewer lateral branches due to defects in the initiation of axillary meristems. The transcription factors CUC2 and CUC3, which regulate the axillary meristem initiation, directly bind to the DA1 promoter and activate its expression. Further results show that the ubiquitin specific protease UBP15, which is a direct substrate of DA1 peptidase, represses the initiation of axillary meristems. Genetic analyses support that CUC2/3, DA1, and UBP15 function, at least in part, in a common pathway to regulate the initiation of axillary meristems. Therefore, our findings discover a novel genetic and molecular framework by which the CUC2/3-DA1-UBP15 regulatory module controls the initiation of axillary meristems, thereby determining plant architecture.