This paper presents a numerical study to investigate delayed ettringite formation (DEF) that may pose a long-term durability risk by altering the microstructure with consequent swelling leading to cracking. A chemo–thermal model is used to predict the evolution and distribution of temperature and hydration phases in a wide range of blended cements. In particular, the influence of nuclear waste loading, waste package size, and the addition of supplementary cementitious materials (SCMs) on DEF is systematically and numerically investigated. The analyses show that higher amounts of ordinary Portland cement (OPC) and waste loadings result in higher hydration temperatures and consequently increased DEF potential by enhancing sulfoaluminate dissolution and hydrogarnet precipitation. Partial replacement of OPC with SCMs reduced hydration heat and mitigated DEF risks. The analysis indicated that the DEF evolution may be different for waste packages of different sizes due to a shift from sulfate-controlling to aluminate-controlling reactions at high temperatures. Interestingly, higher temperatures did not necessarily induce higher DEF potential due to the excessive precipitation of aluminates in the form of hydrogarnet. This research enriches our understanding of DEF’s complex behavior, providing valuable insights for engineering applications beyond civil engineering, such as nuclear waste conditioning.