A full-scale dissimilar metal weld safe-end mock-up, precisely replicating a critical component of a modern nuclear power plant, was investigated. The brittle fracture behavior, carbide evolution and nanoscale elemental segregation in the heat-affected zone (HAZ) of low alloy steel (LAS) were analyzed under both post-weld heat-treated and thermally-aged conditions (400 °C for 15,000 h, equivalent to 90 years of operation) using analytical electron microscopy and atom probe tomography. The observed increase in grain boundary (GB) decohesion and intergranular cracking on the fracture surface and the decrease of fracture toughness are primarily attributed to P and Mn segregation to GBs and the coarsening of carbides upon long-term thermal aging. The direct observations of significant elemental segregation to GBs and the consequent reduction in fracture toughness in the HAZ are unexpected for modern low-phosphorus LASs, highlighting potential concerns for evaluating the structural integrity of modern nuclear power plants.