<p>Protogynous sex change in teleosts involves dramatic gonadal restructuring, governed by the hypothalamic-pituitary-gonadal (HPG) axis. Here, we established the dynamic regulatory atlas of the HPG axis during natural sex change in protogynous orange-spotted grouper (<i>Epinephelus coioides</i>) through multi-tissue transcriptomics. Profiling hypothalamus, pituitary, and gonad tissues across ovarian, intersex, and testicular stages revealed minimal transcriptomic changes in the hypothalamus during ovarian-to-intersex transition but significant differential expression during intersex-to-testis progression. The pituitary showed pronounced activation during the intersex stage featuring <i>fshb</i> and <i>cga</i> upregulation, positioning FSH as a potential trigger of sex change. Gonadal transformation involved extensive transcriptional rewiring during sex change, with induction of male-determination genes (<i>dmrt1</i>, <i>amh</i>) and suppression of female pathways (<i>cyp19a1a</i>, <i>foxl2</i>). Weighted gene co-expression network analysis identified stage-specific modules: an intersex gonad-specific module enriched for p53 signaling and oocyte meiosis pathways may facilitate ovarian regression through apoptosis and cell-cycle arrest where hub genes <i>kpna2</i> and <i>patl2</i> providing mechanistic insights into ovarian atresia, while a testis-specific module enriched for nucleic acid metabolism and spermatogenesis. This integrated multi-tissue analysis reveals how HPG axis coordination drives protogynous sex change, providing a foundation for future mechanistic studies.</p>