Alkali-silica reaction (ASR) is a degradation mechanism that affects a variety of reinforced concrete (RC) structures and has been observed in multiple operating nuclear plants. To ensure safe long-term operation of nuclear reactors, it is essential to quantify the adverse impacts of ASR on the performance of critical nuclear power plant RC structures such as containment vessels (CVs) under seismic loading. The mechanisms driving ASR progression involve coupled physical phenomena, and there is still limited understanding of the effects of ASR on the integrity of CVs under seismic loading. This study utilizes a fully coupled multiphysics model run using an open-source code on a high-performance computer to simulate RC CV performance, capturing the interactions between thermal and moisture transport and the mechanical stress states during ASR progression, as well as the effects of ASR on the CV’s seismic response. The seismic performance of degraded and pristine vessels was evaluated using incremental dynamic analysis (IDA) on a suite of ground motion records. Fragility functions derived from the IDA for functional and collapse limit states provide indicators of the CV’s ability to maintain leak tightness and structural integrity. These fragility functions show a higher probability of exceeding the functional limit state with the ASR-degraded vessel, which could indicate an increased risk of contaminant release due to ASR. ASR has a minimal impact on the median collapse capacity of the CV, but increases its uncertainty.