Pigment epithelium-derived factor (PEDF) is one of the adipocytokines with multifaceted functions, which may serve a role in the development of various types of cardiometabolic disorders. Advanced glycation end products (AGEs) have been shown to contribute to numerous aging-associated disorders, such as cancer. However, it remains unclear whether and how PEDF exerts antitumor effects in AGE-exposed human breast cancer MCF-7 cells, and therefore this was explored in the present study. NADPH oxidase activity was measured with luciferase assay, while gene and protein expression levels were evaluated with quantitative PCR and western blot analysis, respectively. AGEs significantly increased NADPH oxidase-driven superoxide generation, cytochrome b-245 β chain (gp91phox) and receptor for AGE (RAGE) mRNA expression, proliferation, mRNA and protein expression levels of vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-9 mRNA expression in MCF-7 cells, all of which were dose-dependently inhibited by PEDF. Neutralizing antibody against laminin receptor (LR-Ab) significantly blocked these beneficial effects of PEDF in AGE-exposed MCF-7 cells. Furthermore, as in AGE-treated cells, PEDF dose-dependently inhibited the NADPH oxidase-driven superoxide generation, gp91phox, RAGE and MMP-9 mRNA expression, proliferation, mRNA and protein expression levels of VEGF in non-treated control MCF-7 cells, and these effects were also reversed by LR-Ab. LR levels were not affected by the treatment with AGEs, PEDF or LR-Ab. The present study suggested that PEDF may exert antitumor effects in AGE-exposed breast cancer cells by suppressing NADPH oxidase-induced ROS generation and VEGF and MMP-9 expression via interaction with LR. Since PEDF expression is decreased in breast cancer tissues, pharmacological upregulation or restoration of PEDF may inhibit the growth and metastasis of breast cancer.