Increasing production and use of engineered nanoparticles (NPs) leads to their release into the aquatic environments where they can interact with other hazardous contaminants, such as heavy metals, and threaten aquatic organisms. This study considers the ecotoxicity of arsenic (III) and silica nanoparticles (nSiO2), individually and simultaneously to the zebrafish (Danio rerio) using response surface methodology (RSM) under central composite design (CCD). The results revealed that in the treatments within the concentration range of 1 to 5 mg L-1 arsenic and 1-100 mg L-1 nSiO2, no mortality was observed after 96 h. The optimal conditions for achieving the lowest effect of simultaneous toxicity in the concentration range of nSiO2 and arsenic were 100 and 7 mg L-1, respectively. Accordingly, the desirable function of the predicted model was found to be 0.78. According to these results, arsenic is toxic for zebrafish. Importantly, exposure to nSiO2 alone did not cause acute toxicity in the studied species, while arsenic toxicity decreased by increasing the concentration of nSiO2.