It was previously thought that ncRNA could not encode polypeptides, but recent reports have challenged this notion. As research into ncRNA progresses, it is increasingly clear that it serves roles beyond traditional mechanisms, playing significant regulatory roles in various diseases, notably cancer, which is responsible for 70% of human deaths. Numerous studies have highlighted the diverse regulatory mechanisms of ncRNA that are pivotal in cancer initiation and progression. The role of ncRNA-encoded polypeptides in cancer regulation has gained prominence. This article explores the newly identified regulatory functions of these polypeptides in three types of ncRNA-lncRNA, pri-miRNA, and circRNA. These polypeptides can interact with proteins, influence signaling pathways, enhance miRNA stability, and regulate cancer progression, malignancy, resistance, and other clinical challenges. Furthermore, we discuss the evolutionary significance of these polypeptides in the transition from RNA to protein, examining their emergence and conservation throughout evolution.