Downhole high-temperature and high-pressure (HTHP) conditions can cause significant deteriorations of well cement, posing a major risk to wellbore integrity. A comprehensive experimental program is designed to investigate the long-term physical and mechanical property stability of silica-enriched Portland cement (SEPC) systems and various influencing factors. Formulations representing three different densities and two silica dosages are designed for two different curing regimes commonly adopted in the literature: 1) direct high-temperature curing at 240 °C and 2) 80 °C low-temperature pre-curing followed by high temperature curing at 240 °C. Under the direct-curing regime, SEPC systems containing 70% silica undergoes progressive microstructural coarsening and strength retrogression over time. The gradual transformation of tobermorite into xonotlite and other crystal phases, as well as potential structural changes in amorphous C–S–H, both causing reductions in bound water content in hydration products, are the principal factors driving strength retrogression. In contrast, under the pre-curing regime, the tobermorite and bound water contents remain stable or increase progressively with curing time, which lead to significant improvements in their physico-mechanical properties during long term curing. Compared to SEPC systems containing 70% silica, the SEPC systems with 40% silica exhibit improved strength stability and comparable long-term strength but lower initial strength, higher porosity and permeability, due to the generation of large amounts of xonotlite as the main hydration product. Decreasing cement slurry density by increasing water to solid ratio promotes the formation of more crystalline phases, which leads to significantly higher porosity and permeability as well as lower strengths with similar long-term retrogression behavior.