In oocyte to embryo transition, the fertilized oocyte undergoes final maturation and the embryo genome is gradually activated during the first three cell divisions. How this transition is coordinated and which factors drive the processes in humans is largely unknown. Here we studied the role of the double homeodomain transcription factor DUX4 in regulating the human oocyte to embryo transition. DUX4 knockdown zygotes show delayed transcriptome reprogramming during the first three days after fertilization. Our combined experimental approaches allowed integrated analysis on the transcriptome, chromatin, and proteome data in human embryos or a DUX4 expressing human embryonic stem cell model. We conclude that DUX4 is a pioneering factor that regulates human oocyte to embryo transition through regulating oocyte mRNA degradation, as well as direct binding and activation of minor genome activation genes, and genomic repeat elements.