Pinctada maxima is a pearl oyster species producing large, high-quality marine pearls. However, juvenile mortality (shell length < 5 cm) in this species adversely affects commercial pearl production. Understanding the molecular mechanism and genes related to mass mortality will help mitigate this problem. Therefore, the present study investigated the transcriptomic and metabolic differences between pearl oysters during high mortality (HM) and after this period (PD) to shed light on the causes of juvenile mass mortality. Initial analysis of biochemical parameters revealed that protease, α-amylase, and catalase activities in the hepatopancreatic tissues of pearl oysters at the HM stage were significantly lower than at the PD stage. Conversely, glutathione and lysozyme contents, and superoxide dismutase, acid phosphatase, alkaline phosphatase activities were notably higher at the HM stage than at the PD stage. Metabolomic analysis identified 98 metabolites in the adductor muscle significantly different between the two stages, which enriched glycerophospholipid metabolism, glutathione metabolism, arachidonic acid metabolism, oxidative phosphorylation, and neuroactive ligand-receptor interaction pathways. Transcriptome analysis identified 677 differentially expressed genes in the adductor muscle between these stages, which enriched neuroactive ligand-receptor interaction, glutathione metabolism, and ECM-receptor interaction pathways. Finally, an integrated analysis of the metabolome and transcriptome suggested that pearl oysters at the HM stage experience oxidative stress, activate immune-related genes, and exacerbate the low energy status. These findings on the causes of mass mortality lay a theoretical foundation for improving the survival rate of juveniles and advancing the industrialization of P. maxima.