Vibrio parahaemolyticus is a halophilic, Gram-negative bacterium found in marine and estuarine ecosystems and is a significant contributor to seafood-related bacterial gastroenteritis. Cyclic di-GMP (c-di-GMP) is a widespread secondary messenger that modulates various cellular pathways, including virulence factor production, motility, and biofilm formation. c-di-GMP is made by diguanylate cyclases (DGCs), while its breakdown is mediated by phosphodiesterases (PDEs). Although many putative DGCs and PDEs involved in c-di-GMP metabolism have been identified in V. parahaemolyticus, only a few have been thoroughly studied. Furthermore, the metabolism of c-di-GMP is influenced by various environmental factors and transcriptional regulators. This review provides an overview of the c-di-GMP signaling network in V. parahaemolyticus, focusing on recent advancements related to c-di-GMP metabolic enzyme genes and their regulatory mechanisms. Understanding the intricate mechanisms of c-di-GMP metabolism and regulation is crucial for revealing the environmental adaptation and pathogenic strategies of V. parahaemolyticus.