Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a critical role in cancerous processes as either oncogenes or tumor suppressor genes. Here, we demonstrated that lncRNA-PRLB (progression-associated lncRNA in breast cancer) was upregulated in human breast cancer tissues and breast cancer cell lines. Further evaluation verified that lncRNA-PRLB was positively correlated with the extent of metastasis, and its expression was correlated with shorter survival time of breast cancer patients. We identified microRNA miR-4766-5p as an inhibitory target of lncRNA-PRLB. Both lncRNA-PRLB overexpression and miR-4766-5p knockdown could remarkably enhance cell growth, metastasis, and chemoresistance. We also determined that sirtuin 1 (SIRT1) was an inhibitory target of miR-4766-5p, and that SIRT1 was inhibited by both lncRNA-PRLB knockdown and miR-4766-5p overexpression. Significantly, we found that the promotion of cell proliferation and metastasis, the acquisition of chemoresistance, and the increased expression of SIRT1 induced by lncRNA-PRLB overexpression could be partly abrogated by ectopic expression of miR-4766-5p. Taken together, our findings indicated that lncRNA could regulate the progression and chemoresistance of breast cancer via modulating the expression levels of miR-4766-5p and SIRT1, which may have a pivotal role in breast cancer treatment and prognosis prediction.