Endocrine therapies effectively treat breast cancer (BC), but resistance to treatment is common. Currently, 214 clinical trials are registered to assess the impact of fasting on BC outcome, and animal studies as well as phase II clinical trials revealed that fasting enhances endocrine treatment efficacy. However, the underlying mechanisms thereof remain unclear. Furthermore, treating BC patients with caloric restrictive diets while undergoing long-term endocrine treatments, imposes a severe impact on quality-of-life. Thus, we aim to understand the mechanisms underlying the beneficial effects of fasting on endocrine treatment. For that, MCF7 cells were xenografted in mice, treated with tamoxifen alone, or combined with fasting and tumors were isolated. Epigenetic profiling revealed changes in enhancer activity upon fasting in tamoxifen-treated animals, where fasting-associated enhancers were enriched for glucocorticoid receptor (GR) and progesterone receptor (PR) chromatin binding. Interestingly, patient plasma analyses revealed increased corticoid levels upon fasting, while immunohistochemistry on xenografted tumors showed increased GR nuclear staining in fasted mice. Furthermore, transcriptomic analyses showed that GR is specifically activated in tamoxifen treated tumors upon fasting. GR is known to serve as tumor suppressor in BC, providing a plausible mechanism for the tumor-suppressive effects of fasting. To test this, we knocked-out GR from MCF7 cells and xenografted it in mice, which abrogated the observed synergy of tamoxifen with fasting. Moreover, dexamethasone treatment of the mice recapitulated the fasting effects, in combination or not with tamoxifen. Jointly, our data reveal that fasting increases systemic cortisol levels and activates GR, leading to an epigenetic tumor reprogramming to synergize with tamoxifen and block tumor growth. These results position GR-agonists as possible adjuvant systemic treatment in combination with tamoxifen in BC, phenocopying a clinically beneficial –yet challenging to adhere to- lifestyle intervention in BC patients.