Multidrug resistance (MDR) appears to be a major challenge in cancer treatment, frequently leading to suboptimal clinical results and treatment failure. A transmembrane efflux pump called P-glycoprotein (P-gp) is essential to multidrug resistance because it actively transports various chemotherapeutic drugs out of cancer cells, lowering their intracellular concentrations and efficacy. To improve treatment approaches, it is essential to comprehend the structural and functional dynamics of P-glycoprotein and the genetic and epigenetic processes controlling its expression. From the early-generation drugs with poor clinical outcomes to the creation of new medications with enhanced selectivity, potency, and safety profiles, this article thoroughly summarizes the development of P-glycoprotein inhibitors. Enhancing medication bioavailability and overcoming P-glycoprotein-mediated efflux may be possible through the integration of sophisticated drug delivery methods, such as micellar formulations, liposomes, nanoparticles, and polymer-based carriers. Meanwhile, the rise of personalized medicine provides a revolutionary way to manage multidrug resistance through identifying biomarkers, genetic and proteomic characterization, and medication modification for each patient. Advanced tactics such as RNA interference, CRISPR-mediated gene editing, immunotherapeutic therapies, and tumor microenvironment modulation significantly broaden the options to counter multidrug resistance. While highlighting current difficulties, case studies and clinical examples also illustrate translational achievements. In addition to highlighting recent advancements, the present research points out important constraints and suggests potential paths for more potent, focused multidrug resistance cancer treatments.