Significance Metronomic dosing has been proposed as an alternative to maximum tolerated doses of chemotherapy. Even though this strategy has shown promise in improving therapeutic outcomes in some cases, the underlying mechanisms of action are not fully understood. In this study, using mathematical modeling, we show that metronomic chemotherapy could be beneficial by normalizing tumor blood vessel function and improving tumor perfusion. Improved perfusion enhances the delivery of drugs to solid tumors and alleviates hypoxia. These effects also result in an improved immune response, contributing to increased killing of cancer cells, including more resistant cancer stem-like cells.