Abstract: Aberrant activation of oncogenes is a key driver of the initiation and progression of malignant tumors, and intervening in their expression process has become an important anticancer strategy. G-quadruplex (G4) is a type of atypical nucleic acid secondary structure that is widely enriched in the promoter regions and non-coding regulatory elements of various oncogenes, playing a crucial role in the regulation of gene transcription. In recent years, numerous small molecules targeting G4 have been found to interfere with the expression of “undruggable” oncogenes. Therefore, the G4 structure is considered a potential breakthrough for achieving chemical intervention in “undruggable” oncogenes. This review summarizes the research progress of small molecule ligands targeting oncogene G4, and systematically outlines the structural types of related ligands and their mechanisms of action, aiming to provide some reference for the discovery of potential anticancer drugs targeting the G4 structure.