Tbx3 has been identified as a regulator of fate decisions during liver development in the mouse, but whether it function similarly in humans remains unclear. We generated TBX3 knockout human pluripotent stem cell (PSCs) lines using CRISPR/Cas9 genome editing technology. We differentiated TBX3 knockout lines to hepatocytes and found a decrease in hepatic markers and in hepatocyte function, demonstrating that TBX3 is also important for liver differentiation in humans. Surprisingly, we detected expression of pancreatic markers, including PDX1 in our TBX3 knockout hepatocytes, suggesting the possibility that TBX3 may regulate liver development by suppressing a pancreatic fate. We next differentiated the TBX3 knockout lines to pancreatic progenitors to determine whether the loss of TBX3 impacts pancreatic differentiation. We found that TBX3 knockout PSCs generated more pancreatic progenitors, and that these progenitors had an enhanced pancreatic gene expression signature at the expense of hepatic gene expression. We also found that epithelial-to-mesenchymal transition was commonly dysregulated in TBX3 mutant pancreas and hepatocyte cells. This suggests that TBX3 may function during EMT in both liver and pancreas development. These data highlight a potential role of TBX3 in distinguishing between hepatic and pancreatic domains during foregut patterning, with implications for enhancing the generation of pancreatic progenitors from PSCs.