Nuclear factor kappa B (NF-κB) is involved in various important biological processes, such as inflammation, apoptosis, and cell proliferation. Here, we analyzed the function of NF-κB in transplantation immunity and pearl formation using its inhibitor, pyrrolidinedithiocarbamic acid (PDTC), in the pearl oyster Pinctada fucata martensii. The levels of pro-inflammatory factors (IL-17 and TNF-α) were lower and activity of antioxidant-related enzymes was higher in the transplanted pearl oysters pre-treated with PDTC than in transplanted pearl oysters pre-treated with phosphate-buffered saline (PBS). Transcriptomic analysis showed that PDTC pre-treatment alleviated the immune stimulation caused by transplantation, preserved normal expression of ribosome-related genes, and inhibited the activation of apoptosis and the NF-κB signaling pathway induced by transplantation. Additionally, RIG-I-like receptor, MAPK, Toll-like receptor and NOD-like receptor signaling pathways were inhibited after PDTC treatment. A 30-day pearl cultivation experiment demonstrated a significantly higher nucleus retention rate in transplanted pearl oysters that were pre-treated with PDTC compared to the control group. These results indicate that PDTC treatment suppressed immune-related pathways, thereby alleviating the immune rejection response caused by transplantation and potentially optimizing pearl production. Our results provide valuable information for optimizing pearl cultivation in P. f. martensii.