Abstract: Breast cancer (BC) has become the most prevalent cancer worldwide, and BC patients have the highest rate of depression of all cancer patients. However, previous studies, especially studies based on clinical sample data, have failed to reveal exactly how depression affects BC. Two-sample Mendelian randomization (TSMR) was used to determine the causal relationship between depression and BC. Transcriptomics and metabolomics were used to analyze BC samples from nondepressed and depressed patients and to validate differentially expressed genes and key metabolites in vitro. Molecular docking techniques were used to identify compounds that regulate key targets and validate the functions of the compounds in in vitro and in vivo animal models. Depression was identified as a risk factor for BC by the TSMR analysis. On the basis of clinical samples, for the first time, we identified PPARγ and norepinephrine (NE) as key genes and metabolites that mediate the pro-BC effects of depression. In addition, we demonstrated that quercetin can target PPARγ and reverse the procancer effects of PPARγ inhibition mediated by chronic stress in BC cells. Moreover, we found that PPARγ may be associated with the inhibition of CD8 + T cells in the tumor immune microenvironment. In conclusion, depression can increase the infiltration level of NE in tumors and inhibit the expression of PPARγ in tumor cells, thus promoting the proliferation of BC cells and inhibiting the infiltration of CD8 + T cells in the immune microenvironment, ultimately leading to accelerated tumor growth. Quercetin can target PPARγ and reverse this cancer-promoting process.