Sin3 associated protein 18 (SAP18) is an evolutionary conserved protein, originally discovered in a complex with the transcriptional regulatory protein, Sin3. Subsequent investigations revealed SAP18 as an integral splicing component of the exon junction complex (EJC)‐associated apoptosis‐and splicing‐associated protein (ASAP)/PNN‐RNPS1‐SAP18 (PSAP) complex. In association with Sin3, SAP18 contributes toward transcriptional repression of genes implicated in embryonic development, stress response, human immunodeficiency virus type 1 replication, and tumorigenesis. As a part of EJC, SAP18 mediates alternative splicing events and suppresses the cryptic splice sites present within flanking regions of exon–exon junctions. In this review, we provide a thorough discussion on SAP18, focussing on its conserved dual role in transcriptional regulation and messenger RNA splicing. Recent research on the involvement of SAP18 in the emergence of cancer and human disorders has also been highlighted. The potential of SAP18 as a therapeutic target is also discussed in these recent studies, particularly related to malignancies of the myeloid lineage. Significance Statement: This review is to comprehensively highlight the functional role of protein Sin3 associated protein 18 (SAP18) in transcriptional regulation and messenger RNA (mRNA) splicing. In addition to initial studies that focus on SAP18's physiological role as a transcriptional regulator, recent studies have recognized the prominent and conserved role for SAP18 in mRNA processing as a member of the apoptosis‐and splicing‐associated protein/PNN‐RNPS1‐SAP18 splicing complexes. Despite a decade of research on SAP18, its dual role remains poorly understood, particularly in pathological conditions. A crucial role of SAP18 in regulation of human diseases and malignancies has widely emerged, pointing toward SAP18 as a possible therapeutic target. Hence, we provide a consolidated review on SAP18 and the knowledge gaps therein, anticipating the information will be advantageous in future investigations. [ABSTRACT FROM AUTHOR]