Herein, Clean powders of pre-alloyed GH4099 alloy was firstly prepared via plasma rotating electrode process (PREP), which was subsequently consolidated into powder metallurgy alloy using hot isostatic pressing (HIP). The aquired powders exhibited a normal particle size distribution and good sphericity, whilst, the room and high temperature tensile properties of powder metallurgy alloy reach the level of the corresponding wrought alloy. Electron beam welding (EBW) was employed to join the powder metallurgy alloy, and the microstructure of the welded joints, both as-welded and heat-treated state, was characterized using optical microscopy (OM), scanning electron microscopy (SEM), and electron probe micro-analyzer (EPMA). Mechanical properties and residual stress distribution of the joints were also evaluated. The results indicated that heat treatment significantly enhanced the uniformity of the microstructure of the welded joints, promoted the precipitation of strengthening phases, and facilitated a more uniform distribution of elements, effectively reducing post-weld residual stress concentration at the same time. Both of two heat treatment procedures improved the hardness and room temperature tensile strength of the joints, bringing them close to the level of base metal, and also significantly improved the high-temperature ductility. Furthermore, a finite element model was established to predict the residual stress evolution for EMB joints of GH4099 powder metallurgy alloy. The simulation results were consistent with the measured stress distribution.