Abstract: Twig blight disease has the characteristics of strong infectivity and rapid onset, which has brought great losses to the production of bayberry fruit. Lignin-based materials are widely used in the field of nanomedicine delivery due to their wide source, low price, and more active functional groups. In order to seek agents with slow-release function for better control of twig blight disease, Di@BLS nanoparticles were prepared by hydrophobically modifying sodium lignosulfonate (LS) and loading difenoconazole (hereafter referred to as Di) as a test agent, which was characterized by ¹H nuclear magnetic resonance (¹H NMR), fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), dynamic light scattering laser particle sizing (DLS), and the stability of the samples was analyzed by turbiscan stability analyzer (TSI); Di in leaves was extracted by QuEChERs method, and the uptake and translocation of Di@BLS in bayberry were investigated, and finally, diseased branches of bayberry collected for the isolation and identification of pathogenic fungi were carried out. The inhibitory effect of Di@BLS on the bayberry twig blight disease was investigated using the mycelial growth rate method and the pot experiment, respectively. The results showed that the average particle size of Di@BLS was 135.2 nm at a BLS carrier concentration of 1%, a feed/drug ratio of 5 : 1 and a SDS dosage of 0.2% by mass. The optimized formulation could maintain stability similar to that of Di ME while reducing the amount of surfactant. Both absorption transfer and field experiments confirmed that Di@BLS could delay drug degradation and persist longer in bayberry than Di ME. The results of the mycelial growth rate method showed that the EC₅₀ value of Di@BLS against Lasiodiplodia was 0.643 μg/mL, which is close to that of Di ME. In the pot experiment, at the mass concentration of 200 μg/mL, Di@BLS could reduce the incidence of blight of bayberry by 2.3% compared with Di ME. The results showed that the prepared nanoparticles Di@BLS had a long duration and good antifungal effect in bayberry, which provided a theoretical basis for the prevention and control of twig blight disease of bayberry.