Significance Despite initial responsiveness to chemotherapy, the overwhelming majority of advanced ovarian cancer patients relapse with resistant disease. Thus, developing more effective strategies for ovarian cancer treatment is a high clinical priority. Here, we report that targeting angiotensin signaling with losartan, an angiotensin receptor blocker, can reduce extracellular matrix in ovarian tumors and the associated physical barriers that normally hinder drug delivery and efficacy. These changes in the tumor microenvironment lead to improved response to chemotherapy, and, importantly, decrease ascites—a major burden for ovarian cancer patients. These preclinical findings are in concert with our retrospective analysis showing improved survival in patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer and should be tested in a clinical trial.