Significance Although MK2 inhibition has been proposed as a therapy in cancer, its exact role, as well as the cellular and molecular mechanisms underlying it, in the intestine is not known. Here, we show that complete MK2 deletion leads to decreased epithelial cell proliferation, associated with reduced tumor growth and invasive potential in the Apc min/+ and colitis-associated cancer model. Notably, this function of MK2 is not mediated by its well-described immunomodulatory roles in inflammatory cells. Instead, MK2 modulates tumor progression mainly via modulating mesenchymal-specific Hsp27-mediated activation of protumorigenic mediators. Our results advance our understanding of mesenchymal MAPK signaling in intestinal cancer progression and demonstrate the value of MK2 inhibition in the treatment of cancer.