Adipocyte-derived leptin activates multiple oncogenic signaling, leading to breast cancer cell progression and metastasis. Hence, finding effective strategies to inhibit the oncogenic effects of leptin would provide a novel approach for disrupting obesity-associated breast cancer. In the current study, we explored the role of piperine, a major plant alkaloid from Piper nigrum (black pepper), against leptin-induced breast cancer. Piperine treatment significantly inhibited leptin-induced breast cancer cell proliferation, colony formation, migration, and invasion. We found that piperine downregulated the expression of PPARalpha, a predicted target of miR-181c-3p. Mechanistically, piperine potentiates miR-181c-3p-mediated anticancer potential in leptin-induced breast cancer cells. Interestingly, the knockdown of PPARalpha reduced the proliferative potential of leptin-induced breast cancer cells. Further, oral administration of piperine inhibited breast tumor growth in diet-induced obese mice, accompanied by the upregulation of miR-181c-3p and downregulation of PPARalpha expression. Together, piperine represents a potential candidate for further development as an anticancer agent for treating obesity-associated breast cancer.