Pancreatic cancer has one of the highest fatality rates of all diseases, but poor drug availability after intravenous (IV) administration has hindered the diagnosis and treatment of patients. Herein, the authors report a novel strategy, combining intraperitoneal administration and phosphatidylcholine-camouflaged NaLuF4:Yb, Tm/NaLuF4/NaDyF4 upconversion nanoparticles (UCNP@PC) to gain the enhanced dual-modal imaging (upconversion luminescence/magnetic resonance imaging) of orthotopic pancreatic cancer. Remarkably, the authors observe a 16-fold improvement in the efficacy of utilization promoted intraperitoneally administered UCNP@PC in monitoring orthotopic pancreatic cancer compared with IV approach. Benefiting from modification with phosphatidylcholine, a major component of cell membranes, the optimized nanostructures show excellent biocompatibility and are rapidly excreted via the bile pathway after their intraperitoneal administration. The integration of the advanced design of UCNP@PC and the optimal drug administration route also give a general strategy for the advanced diagnosis and treatment of a series of intraperitoneal cancers.