The evaluation of eco-toxicity of ionic liquids (ILs) in the aquatic environment is essential for their safe utilization and QSTR approach plays an important role in obtaining the eco-toxicity data of ILs with diverse structures. Usually, the descriptors used to build QSTR model were made up of anion and cation descriptors, and their interactions were often neglected to some extent. In this work, based on the optimization of the ILs structure, a new set of descriptors were proposed to describe the interaction between anions and cations, and some new atomic distribution matrices were constructed to calculate norm descriptors of ILs, anion and cation. A norm index-based QSTR model was built to predict the eco-toxicity of ILs toward Leukemia rat cell line (IPC-81). This model has satisfactory statistical results with the R of 0.954 and RMSE of 0.241, respectively. Furthermore, leave-one-out cross-validation and applicability domain results showed good stability and predictability of this model. This approach showed that the interaction between cations and anions could be reflected by optimizing the whole structure of ILs which might play an important role for describing the eco-toxicity of ILs. Therefore, it is further suggested that the norm descriptors would be applicable to predict the eco-toxicity of ILs towards IPC-81.