Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stromal fibrosis that limits drug delivery and promotes therapeutic resistance. Pancreatic stellate cells (PSCs), key mediators of desmoplasia, represent a promising yet underexploited therapeutic target. This study aimed to suppress PSC activation and remodel tumor stroma by silencing fibroblast growth factor 19 (FGF19) using a reactive oxygen species (ROS)-responsive small interfering RNA (siRNA) delivery system. Methods: A ROSsensitive gold nanoparticle-based nanoplatform was constructed and characterized by transmission electron microscopy and dynamic light scattering. Cellular uptake, gene silencing, and functional effects were evaluated in human PSCs (hPSCs). Fibrosis-related markers were analyzed by Western blot and quantitative polymerase chain reaction. In vivo biodistribution, safety, and antitumor efficacy were assessed in a PANC-1 xenograft model. Results: The nanoplatform exhibited efficient siRNA loading, stability, and ROS-triggered release. Compared with free siRNA, it significantly enhanced intracellular delivery and FGF19 silencing in hPSCs. This resulted in reduced PSC activation, proliferation, migration, and invasion, along with increased apoptosis under oxidative stress. Expression of profibrotic markers, including α-smooth muscle actin, collagen I, and fibronectin, was markedly downregulated. In vivo, the nanoplatform preferentially accumulated in tumors, showed favorable biosafety, and significantly inhibited tumor growth. Conclusions: ROS-responsive siFGF19 nanotherapy effectively reprograms PSC activation and remodels the fibrotic tumor microenvironment in PDAC. This strategy provides a promising approach for overcoming stromal barriers and improving therapeutic outcomes in pancreatic cancer.