MegaPower reactor is a solid monolithic heat pipe cooled reactor (SMHPR) designed for decentralized electricity market. However, the solid monolithic core has a high thermal stress during the reactor operation and is complex to manufacture. Therefore, an independent fuel element with central heat pipe reactor (ICHPR) design has been proposed to replace the monolithic structure. Besides, both UN and U–10Zr fuels have been suggested to replace the UO2 fuel to reduce the 235U enrichment in MegaPower reactor. In this work, the depletion performances of SMHPR and ICHPR designs with UO2, UN (natural 15N), UN (enriched 15N) and U–10Zr fuels are compared analytically. The results indicate that ICHPR lowers material thermal stress, thermalizes the neutron spectrum, reduces the initial 235U enrichment and MAs production, and improves the 239Pu production relative to SMHPR under the same fuel material and operation time. For these two reactor designs, the U–10Zr core has lower initial 235U enrichment and lower variation range of keff relative to the UO2, UN (natural 15N), and UN (enriched 15N) cores. Though the U–10Zr core produces more minor actinides and long-lived fission products relative to the UO2 and UN (enriched 15N) cores in the spent fuel, the corresponding radiotoxicity difference ratio between the U–10Zr core and other cores is less than 0.9% during the 200 years day time. Therefore, the ICHPR with U–10Zr fuel is recommended for a better MegaPower reactor design.