<p>Multidrug resistance (MDR) poses a significant challenge in cancer treatment by reducing the efficacy of therapies. This review highlights the potential of lyotropic liquid crystals (LLCs) as innovative nanocarrier systems to overcome MDR. LLCs are characterized by their highly ordered internal structures, which can self-assemble into various phases, including lamellar, hexagonal, and cubic geometries. These structures allow LLCs to encapsulate and release cargo with diverse sizes and polarities, making them promising candidates for drug delivery applications. The phase of LLCs—whether cubic, hexagonal, or lamellar—can influence the physicochemical properties of encapsulated drugs, enabling tailored release profiles such as sustained, controlled, or targeted delivery. This review also explores the transitions in molecular geometry of amphiphilic compounds, additives, and hydrotrope molecules, which affect the formation and stability of LLC phases with varying pore sizes and water channels. The conclusion underscores the importance of ongoing research into LLCs for addressing cancer treatment challenges, including MDR. The versatility of LLCs extends beyond drug delivery to theranostic and diagnostic applications. By leveraging responsive smart drug delivery systems or incorporating natural compounds, LLCs offer a multifaceted approach to cancer therapy, highlighting their potential as a breakthrough in the field.</p> Graphical Abstract <p></p>