Abstract: Nuclear safeguards remain a topic of shared concern for the international community. Large geometry secondary ion mass spectrometry (LG-SIMS) has been employed to efficiently analyze uranium `isotopes in uranium particle samples for monitoring undeclared nuclear activities. To establish an accurate uranium isotopic analysis method for uranium particles, LG-SIMS instrumentation was utilized in this research. Instrument parameters and experimental conditions were optimized using U010 certified reference material (U010 standard) as the test subject. Firstly, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) were performed to characterize the morphology and elemental composition of the standard material. Next, key instrument parameters and experimental conditions were optimized, including ion source voltage intensity, primary ion beam intensity, optical transmission system settings, entrance slit, exit slit, energy slit, and the intensity and position of the mas spectral peaks of target ions. Finally, based on the U010 standard, a LG-SIMS method for uranium isotopic analysis of uranium particles was established. The results indicate that the measured ratios of ²³⁴U/²³⁸U, ²³⁵U/²³⁸U, and ²³⁶U/²³⁸U agree with the certified values within analytical uncertainty. The relative deviations of δ(²³⁴U/²³⁸U), δ(²³⁵U/²³⁸U), and δ(²³⁶U/²³⁸U) are 1.28%, 0.33%, and 0.41%, respectively, meeting and exceeding the required technical specifications. For the single δ(²³⁶U/²³⁸U) result from the second LG-SIMS test that fell below the technical threshold, the primary contributing factors were identified as that the interference from uranium hydride ions (²³⁵U¹H⁺) on the ²³⁵U⁺ ion signal and the interference from impurities surrounding the particle sample. In summary, the uranium isotopic analysis of uranium particles using the LG-SIMS platform is technically feasible and methodologically sound. This work provides robust technical support for China’s role in enhancing nuclear security.