Individuals with pancreatic cancer have one of the poorest survival rates among the major cancers, suggesting the need to develop new therapeutic approaches. An effective animal model that mimics the progression and metastases of human pancreatic adenocarcinoma does not exist. The goal of this investigation was to develop a model that would compare the growth and metastasis of orthotopically injected pancreatic cancer cells to cells encapsulated within a synthetic extracellular matrix (sECM). The hypotheses tested were that the cells within the sECM would grow more quickly and more frequently develop metastasis to distant organs. MiaPaCa-2 cells expressing red fluorescent protein, either in serum-free media or within a hyaluronan-based hydrogel, were injected into the pancreas of nude mice. Tumors were monitored for 8 weeks via intravital red fluorescent protein imaging. Cells encapsulated within the sECM grew more quickly and produced larger tumors compared with the cells alone. In addition, the cells within the sECM developed metastasis more frequently. Therefore, the encapsulation of human pancreatic cancer cells within an injectable sECM improved the rate of tumor growth and metastasis in an orthotopic mouse model. The advantages of this new approach can be utilized to investigate the mechanisms of tumor progression and test novel therapeutic agents in vivo.