Pressure resistance welding is usually used to seal the connection between the cladding tube and the end plug made of zirconium alloy. The seal welded joint has a direct effect on the service performance of the fuel rod cladding structure. In this paper, the pressure resistance welded joints of zirconium alloy tube-plug structure were obtained by thermal-mechanical simulation experiments. The microstructure and microhardness of the joints were both analyzed. The effect of processing parameters on the microstructure was studied in detail. The results showed that there was no β-Zr phase observed in the joint, and no obvious element segregation. There were different types of Widmanstätten structure in the thermo-mechanically affected zone (TMAZ) and heat affected zone (HAZ) of the cladding tube and the end plug joint because of the low cooling rate. Some part of the grains in the joint grew up due to overheating. Its size was about 2.8 times that of the base metal grains. Due to the high dislocation density and texture evolution, the microhardnesses of TMAZ and HAZ were both significantly higher than that of the base metal, and the microhardness of the TMAZ was the highest. With the increasing of welding temperature, the proportion of recrystallization in TMAZ decreased, which was caused by the increasing of strain rate and dislocation annihilation.