Transglutaminase 2 (TG2) is a key cancer cell survival protein in many cancer types. As such, efforts are underway to characterize the mechanism of TG2 action. In the present study we report that TG2 stimulates CD44v6 activity to enhance cancer cell survival via a mechanism that involves formation of a TG2/CD44v6/ERK1/2 complex that activates ERK1/2 signaling to drive an aggressive cancer phenotype. TG2 and ERK1/2 bind to the CD44v6 C-terminal intracellular cytoplasmic domain to activate ERK1/2 and stimulate cell proliferation and invasion. This is the same region that binds to ERM proteins and ankyrin to activate CD44v6-dependent cell proliferation and invasion migration. We further show that treatment with hyaluronan, the physiological CD44v6 ligand, stimulates CD44v6 activity, as measured by ERK1/2 activation, but that this response is severely attenuated in TG2 or CD44v6 knockdown or knockout cells. Moreover, treatment with TG2 inhibitor reduces tumor growth and that is associated with reduced CD44v6 level and ERK1/2 activity, and reduced stemness and EMT. These changes are replicated in CD44v6 knockout cells. These findings suggest that a unique TG2/CD44v6/ERK1/2 complex leads to increased ERK1/2 activity to stimulate an aggressive cancer phenotype and stimulate tumor growth. These findings have important implications for cancer stem cell maintenance and suggest that co-targeting of TG2 and CD44v6 with specific inhibitors may be an effective anti-cancer treatment strategy. Implications: Transglutaminase 2 and CD44v6 are important pro-cancer proteins. TG2 and ERK1/2 bind to the CD44v6 C-terminal domain to form a TG2/CD44v6/ERK1/2 complex which activates ERK1/2 to stimulate the cancer phenotype.