The winged pearl oyster Pteria penguin has the unique stout byssus in comparison with other pearl oysters. However, the mechanism of the byssus secretion in this species has not been largely investigated. This study applied transcriptomic and metabolomic techniques to elucidate this mechanism. The results showed that 3420 differentially expressed genes (DEGs) were identified which were enriched in glycolysis/gluconeogenesis, pentose phosphate pathway, TCA cycle, fatty acid metabolism, mTOR signaling pathway, FoxO signaling pathway and Notch signaling pathway. The metabolomic analysis revealed that 135 significantly different metabolites (SDMs) were identified with 23 pathways involved, including pentose phosphate pathway, glutathione metabolism and amino acid metabolism. Comprehensive analysis of transcriptome and metabolome indicated that glycogen, fatty acid metabolism and protein conversion could be used interchangeably as energy sources. Moreover, the glutathione metabolism and immune response demonstrated the importance of cellular homeostasis for byssus secretion in the winged pearl oyster. Dynamic expression of 5-hydroxytryptamine, dopamine receptors and adenylate cyclase suggested that the foot may regulate byssus secretion through an aminergic neurofeedback system which could translate information into neurochemical signals. In conclusion, this study provided insights into the energy metabolism and signaling regulation of byssus secretion in winged pearl oyster by the transcriptomic and metabolomic analyses.