Abstract: Technetium-99m (^99mTc) is a key medical isotope widely used in diagnostic imaging. It is primarily obtained from the decay of its parent nuclide, molybdenum-99 (⁹⁹Mo). In China, over 80% of nuclear medicine diagnostic procedures rely on ^99mTc-based imaging agents.However, the supply of the raw material, ⁹⁹Mo, currently depends entirely on imports. The dominant production method for ⁹⁹Mo involves the irradiation of uranium-235 (²³⁵U) in nuclear reactors. To expedite the domestic production of ⁹⁹Mo, the Institute of Nuclear Physics and Chemistry of China Academy of Engineering Physics has established a ⁹⁹Mo production line utilizing highly enriched uranium (HEU) targets irradiated in a reactor. This work focuses on the development of HEU targets for ⁹⁹Mo production, with optimization of key process parameters—such as powder mixing duration, die size in cold pressing, and sintering temperature. Comprehensive evaluations were conducted on the dimensional accuracy, leakage rate, and internal microstructure of the fabricated targets. As a result, a robust HEU target fabrication process has been established, which is fully compatible with downstream disassembly and separation-purification steps.