The tumor microenvironment (TME) is crucial in cancer progression, and the extracellular matrix (ECM) is an important TME component. Collagen is a major ECM component that contributes to tumor cell infiltration, expansion, and distant metastasis during cancer progression. Recent studies reported that collagen is deposited in the TME to form a collagen wall along which tumor cells can infiltrate and prevent drugs from working on the tumor cells. Collagen–tumor cell interaction is complex and requires the activation of multiple signaling pathways for biochemical and mechanical signaling interventions. In this review, we examine the effect of collagen deposition in the TME on tumor progression and discuss the interaction between collagen and tumor cells. This review aims to illustrate the functions and mechanisms of collagen in tumor progression in the TME and its role in tumor therapy. The findings indicated collagen in the TME appears to be a better target for cancer therapy.