RNA interference (RNAi) is a mechanism for regulating gene expression through small interfering RNAs (siRNAs), double-stranded RNA molecules approximately 20–23 nucleotides in length. The RNAi holds significant therapeutic potential for suppressing disease-related genes in a sequence-specific manner. Most commercially available siRNAs are extensively chemically modified to enhance stability or reduce immunogenicity. These chemical modifications also play a crucial role in mitigating off-target effects, which primarily arise from unintended interactions between the siRNA seed region (positions 2–8) and non-target mRNAs. Here, we introduce small interfering RNA root-mean-square deviation (siRMSD), a novel parameter that quantifies structural distortions induced by chemical modifications in siRNAs. We demonstrate a strong correlation between deviations from the canonical A-form RNA structure and the reduction in siRNA off-target effect. This approach provides a predictive framework for rational siRNA design, facilitating the development of chemically modified siRNAs with minimized off-target interactions. Our findings contribute to the advancement of more precise and effective RNAi-based therapeutics by elucidating the position-dependent effects of chemical modifications on siRNA off-target effects.