The human placenta plays vital roles in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, however, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here, we conducted integrated snRNA-seq and snATAC-seq on human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their presence in human trophoblast stem cells (hTSCs)-derived STB. Furthermore, we identified transcription factor (TF) motifs that are biased towards diverse STB nuclear lineages through their associated gene regulatory networks. The role of these TFs in STB differentiation were confirmed in the hTSCs- and trophoblast organoid-derived STB. Together, our data provide valuable insights into the heterogeneity of human STB and represents a valuable resource for interpreting its associated pregnancy complications. Overall design: To comprehensively understand the human placental nuclear repertoire and its regulatory mechanisms, we applied snRNA-seq and snATAC-seq techniques to nuclei isolated from six healthy placentas in early pregnancy (10X Genomics; 6-9 weeks of gestation), and six healthy placentas in late pregnancy (10X Genomics; 38-39 weeks of gestation). We took measures to eliminate potential sex-bias by collecting an equal number of placentas on each gender prior sequencing. Equal portions of intact placental nuclei from the same placenta were utilized for snRNA-seq and snATAC-seq