Scientific research in recent decades has affirmed an increase in cancer incidence as a cause of death globally. Cancer can be considered a plurality of various diseases rather than a single disease, which can be a multifaceted problem. Hence, cancer therapy techniques acquired more accelerated and urgent approvals compared to other therapeutic approaches. Radiotherapy, chemotherapy, immunotherapy, and surgery have been widely adopted as routine cancer treatment strategies to suppress disease progression and metastasis. These therapeutic approaches have lengthened the longevity of countless cancer patients. Nonetheless, some inherent limitations have restricted their application, including insignificant therapeutic efficacy, toxicity, negligible targeting, non‐specific distribution, and multidrug resistance. The development of therapeutic oligomer nanoconstructs with the advantages of chemical solid‐phase synthesis, programmable design, and precise adjustment is crucial for advancing smart targeted drug nanocarriers. This review focuses on the significance of the different aptamer‐assembled nanoconstructs as multifunctional nucleic acid oligomeric nanoskeletons in efficient drug delivery. We discuss recent advancements in the design and utilization of aptamer‐tethered nanostructures to enhance the efficacy of cancer treatment. Valuably, this comprehensive review highlights self‐assembled aptamers as the exceptionally intelligent nano‐biomaterials for targeted drug delivery based on their superior stability, high specificity, excellent recoverability, inherent biocompatibility, and versatile functions.