Mesoderm arises from pluripotent epiblasts and differentiates into multiple lineages. However, the molecular mechanisms underlying this process remain unclear. Tbx6 is enriched in paraxial mesoderm and implicated in somite formation, but its function in other mesoderm remains elusive. Here we show Tbx6 induces nascent mesoderm from pluripotent stem cells (PSCs) and determines cardiovascular and somite lineage specification via its temporal expression. Direct reprogramming-based screening identified Tbx6 was a nascent mesoderm-inducing factor. Single-cell RNA-seq in mouse embryos and directed cardiac differentiation in PSCs revealed Tbx6 expression in nascent mesoderm primed to differentiate into cardiovascular lineages. Knockdown of Tbx6 inhibited mesoderm and cardiac differentiation, whereas transient Tbx6 expression induced mesoderm and cardiovascular specification from mouse and human PSCs via direct upregulation of Mesp1, repression of Sox2, and activation of BMP/Nodal/Wnt signaling. Notably, prolonged Tbx6 expression suppressed cardiac differentiation and instead induced somite lineages, including skeletal muscle and chondrocytes. Thus, Tbx6 is critical for mesoderm induction and subsequent lineage diversification.