The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway plays a crucial role in the regulation of autophagy, a cellular mechanism vital for homeostasis through the degradation of damaged organelles and proteins. The dysregulation of this pathway is significantly associated with cancer progression, metastasis, and resistance to therapy. Targeting the PI3K/AKT/mTOR signaling pathway presents a promising strategy for cancer treatment; however, traditional therapeutics frequently encounter issues related to nonspecific distribution and systemic toxicity. Nanoparticle-based drug delivery systems represent a significant advancement in addressing these limitations. Nanoparticles enhance the bioavailability, stability, and targeted delivery of therapeutic agents, facilitating the precise modulation of autophagy in cancer cells. Functionalized nanoparticles, such as liposomes, polymeric nanoparticles, and metal-based nanocarriers, facilitate targeted drug delivery to tumor tissues, minimizing off-target effects and improving therapeutic efficacy. These systems can deliver multiple agents concurrently, enhancing the modulation of PI3K/AKT/mTOR-mediated autophagy and related oncogenic pathways. This review examines advancements in nanoparticle-mediated drug delivery that target the PI3K/AKT/mTOR pathway, emphasizing their contribution to improving precision and minimizing side effects in cancer therapy. The integration of nanotechnology with molecularly targeted therapies presents substantial potential for addressing drug resistance. Future initiatives must prioritize the optimization of these systems to enhance clinical translation and patient outcomes.