Long-term storage of carbon dioxide (CO2) inside depleted reservoirs can help reduce the impact of greenhouse gas emissions. Portland cement has been shown to degrade significantly during long-term contact with CO2. This research aims to provide a new environmentally friendly, Class C fly ash-based cement as a potential alternative to Portland cement for CO2 storage wells. This was achieved by comparing the mechanical degradation of Portland cement and Class C fly ash-based alkali-activated cement in a CO2 environment. A specially designed setup was constructed to create an in situ high pressure and high-temperature CO2 environment. Seventy-two cores of Portland cement and Class C fly ash-based cement were prepared for this study. The results show that CO2 reacted with the water in the vessel and formed carbonic acid, which reduced the water pH to 6.8. Millimeter-sized crystals of calcium carbonate (CaCO3) were observed on the surface of the Portland cement cores after the CO2 exposure. The surface of the fly ash-based alkali-activated cement cores was not substantively changed after the exposure. No significant change in density was observed for both types of cement during the 14 days of CO2 exposure. Portland cement showed a significant reduction in compressive strength, and this reduction developed as the exposure time increased. Interestingly, Class C fly ash-based cement showed no reduction in compressive strength, and only a small amount of reduction was observed after 14 days of exposure. This research compared the mechanical degradation of Portland cement and Class C fly ash-based alkali-activated cement in a high-pressure and high-temperature CO2 environment.