Breast cancer remains a leading cause of morbidity and mortality among women worldwide, posing significant treatment challenges and resistance to conventional chemotherapy, targeted therapy, and immunotherapy, leading to treatment failures. These methods often lack target specificity, leading to significant side effects. Moreover, the development of drug resistance, where breast cancer cells adapt to withstand the effects of treatment, poses a major challenge, frequently resulting in multidrug resistance (MDR). Combining multiple drugs has been a traditional strategy to combat MDR, but it frequently results in severe side effects. Drug resistance in breast cancer arises from mechanisms such as altered drug uptake, enhanced DNA repair, and dysregulated apoptosis pathways. MicroRNAs (miRNAs) play a pivotal role in regulating the cellular processes and have been implicated in both the development and potential reversal of drug resistance. As the understanding of tumor heterogeneity deepens, nanotechnology-based delivery systems such as liposomes, polymeric micelles, nanoparticles, and DNA nanostructures have emerged as promising tools in addressing drug resistance in cancer therapy. These materials offer several advantages, including selective targeting of tumor cells, low toxicity, excellent biocompatibility, ease of preparation, the ability to carry antitumor drugs, and customizable surface functions. Their customizable surfaces allow for the attachment of targeting ligands, improving specificity and reducing off-target effects. Additionally, gene delivery using hybrid and theranostic nanomedicine has also been explored in the treatment. Advancements in nanotechnology have facilitated the effective delivery of miRNAs by improving their stability and targeting specific cells. This chapter reviews the mechanisms of multidrug resistance in breast cancer and its therapeutic targets, structural activity relationship between drug and targets, Recent progressions in the Nanobased drug delivery/ microRNA-based therapies to overcome MDR in breast cancer, functionalized nanomaterials, and a theoretical framework for identifying optimal treatment strategies in the future.