The prognosis of cancer disease is worsened upon shedding of tumor cells from the primary tumor, which escape to the blood stream and form metastases at distant sites within the body. Inhibition of cell shedding from the primary tumor could therefore be exploited to avoid metastasis and delay the progression of the cancer disease. In the present study, we investigated the effects of the polyphenols resveratrol, baicalein, epicatechin, epigallocatechin and polyphenon 60 on cell shedding from multicellular tumor spheroids of the murine mammacarcinoma cell line 4T1, cell invasion into embryonic stem cell-derived tissues, generation of reactive oxygen species (ROS) and expression of matrix metalloproteinase 9 (MMP-9). With increasing tumor spheroid growth MMP-9 expression was upregulated and cells detached from tumor spheroids and formed subspheroids that displayed pronounced ROS generation. Upon incubation with polyphenols tumor growth was arrested and cell shedding was totally abolished. Polyphenol treatment decreased ROS generation and downregulated MMP-9 expression. Furthermore, polyphenols significantly inhibited invasion of tumor cells into embryonic stem cell-derived, vascularized tissues. Our data suggest, that polyphenols inhibit cell shedding and invasion by their anti-oxidative capacity and downregulation of MMP-9 expression.