Multiple-bit upsets (MBUs) have become a threat to modern advanced field-programmable gate arrays (FPGAs) applications in radiation environments. Hence, many investigations have been conducted using medium-energy heavy ions to study the effects of MBU radiation. However, high-energy heavy ions (HEHIs) greatly affect the size and percentage of MBUs because their ionization-track structures differ from those of medium-energy heavy ions. In this study, the different impacts of high-energy and medium-energy heavy ions on MBUs in 28 nm FPGAs as well as their mechanisms are thoroughly investigated. With the Geant4 calculation, more serious energy effects of HEHIs on MBU scales were successfully demonstrated. In addition, we identified worse MBU responses resulting from lowered voltages. The MBU orientation effect was observed in the radiation of different dimensions. The broadened ionization tracks for tilted tests in different dimensions could result in different MBU sizes. The results also revealed that the ionization tracks of tilted HEHIs have more severe impacts on the MBU scales than medium-energy heavy ions with much higher linear energy transfer. Therefore, comprehensive radiation with HEHIs is indispensable for effective hardened designs to apply high-density 28 nm FPGAs in deep space exploration.