Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein of interest (POI) ligand and an E3 ligase ligand connected by a linker, which can recruit POI and E3 ligases simultaneously, thereby inducing the degradation of POI and showing great potential in disease treatment. A challenge in developing PROTACs is the design of linkers and the modification of ligands to establish a multifunctional platform that enhances degradation efficiency and antitumor activity. As a programmable and modifiable nanomaterial, DNA tetrahedron can precisely assemble and selectively recognize molecules and flexibly adjust the distance between molecules, making them ideal linkers. Herein, we developed a multivalent PROTAC based on a DNA tetrahedron, named AS-TD2-PRO. Using DNA tetrahedron as a linker, we combined modules targeting tumor cells, recognizing E3 ligases, and multiple POI together. We took the undruggable target protein signal transducer and activator of transcription 3 (STAT3), associated with the etiology and progression in a variety of malignant tumors, as an example in this study. AS-TD2-PRO with two STAT3 recognition modules demonstrated good potential in enhancing tumor-specific targeting and degradation efficiency compared to traditional bivalent PROTACs. Furthermore, in a mouse tumor model, the superior therapeutic activity of AS-TD2-PRO was observed. Overall, DNA tetrahedron-driven multivalent PROTACs both serve as a proof of principle for multifunctional PROTAC design and introduce a promising avenue for cancer treatment strategies.