The characteristics of seawater sea sand concrete become a recent research issue, while the alkali-silica reaction (ASR) of seawater sea sand concrete is still unclear. To clarify the influence of supplementary cementitious materials on the alkali-silica reaction characteristics of seawater and sea sand concrete, the cement-metakaolin-fly ash-slag cementitious materials were designed by a simplex centroid design method. The effect of supplementary cementitious materials on the ASR products, pore structure, pore solution pH value, alkali ion content and expansion rate of seawater and sea sand concrete was investigated. The results show that the content of the amorphous product ASR-P1(K0.52Ca1.16Si4O8(OH)2.84·1.5H2O) and the crystalline product Na-shlykovite (NaCaSi4O8(OH)3·2.3H2O) in seawater and sea sand concrete are inversely proportional to the content of active SiO2 and Al2O3 in supplementary cementitious materials. Among the seawater and sea sand concretes with different cementitious materials, the pH value of paste prepared with 50% cement+25% metakaolin+25% fly ash and the contents of Na+, K+ and Ca2+ are the minimum values. As a result, the content of ASR-P1 and Na-shlykovite, the content of harmful pores and multi-harmful pores are the minimum values, as well as the porosity is the maximum value, thus resulting in the minimum expansion rate of the paste prepared with 25% metakaolin+25% fly ash +50% cement at 14 d and 28 d. This paper can provide a theoretical basis for the design of cementitious material composition of seawater and sea sand concrete, and improve the service life of seawater and sea sand concrete structure in marine engineering.