Hyaluronan is abundant in the extracellular matrix of many desmoplastic tumors and determines in large part the tumor biochemical and mechanical microenvironment. Additionally, it has been identified as one of the major physiological barriers to the effective delivery of drugs to solid tumors and its targeting with the use of pharmaceutical agents has shown to decompress tumor blood vessels, and thus improve tumor perfusion and efficacy of cytotoxic drugs. In this study, we investigated the contribution of hyaluronan to the accumulation of mechanical forces in tumors. Using experimental data from two orthotopic breast tumor models and treating tumors with two clinically approved anti-fibrotic drugs (tranilast and pirfenidone), we found that accumulation of growth-induced, residual forces in tumors are associated with hyaluronan content. Furthermore, mechanical characterization of the tumors revealed a good correlation of the accumulated forces with the elastic modulus of the tissue. Our results provide important insights on the mechano-pathology of solid tumors and can be used for the design of therapeutic strategies that target hyaluronan.