Plasma gelsolin (pGSN), a protein primarily involved in clearance of circulating actin filaments, is an upcoming novel biomarker. Its level changes in multiple disease and injury conditions, attributable mainly to its consumption during actin clearance; the endogenous regulation of its expression, however, remains elusive as well as unexplored. Here, we are reporting the first isolation of the promoter region of pGSN gene and investigation of its transcriptional regulation during pregnancy (a natural process associated with a well-programmed injury course of parturition). Interestingly, two of the pregnancy-related hormones, human chorionic gonadotrophin (hCG) and progesterone, significantly upregulated pGSN promoter activity in muscle cells. This action of both hormones was found to mediate through their respective cellular receptors and involved a contribution of multiple signaling pathways including those of protein kinase A, protein kinase C, epidermal growth factor receptor and prostaglandin-endoperoxidase synthase 2 in the case of hCG-mediated upregulation. This novel upregulation was further supported by elevated levels of endogenous pGSN transcripts as well as secreted protein upon hormonal treatments of muscle cells compared with untreated controls. A participation of pGSN promoter cis-elements, capable of interacting with endogenous transcription factors, Ap1, Sp1, and p300, was also observed during this hormonal upregulation. Additionally, the augmented pGSN levels observed in pregnant mice compared with the control animals further supported an upregulation of this protein during pregnancy, implicating vital role(s) played by pGSN during this period in mammals.