The spread of Novichok nerve agents and their various chemical forms has presented the international community with considerable challenges in terms of threat assessment and mitigation techniques. This article gives an in-depth look at the use of quantitative structure-activity relationship (QSAR) models to deduce the structure-activity relationships of several Novichok derivatives. QSAR models have emerged as invaluable tools for predicting the toxicological characteristics and reactivity profiles of these strong chemical warfare agents by using a wealth of experimental data combined with improved computational methodologies. The paper also discusses the crucial importance of QSAR techniques in unraveling the complex interplay between chemical structure and biological activity, throwing light on critical molecular properties influencing the cholinergic system, neurotoxicity, toxicity, respiratory failure and skin permeation. QSAR models have shown exceptional prediction accuracy through rigorous validation and refinement, allowing the prioritizing of chemicals for targeted research and the invention of more effective countermeasures. Ultimately, this analysis emphasizes the critical importance of QSAR modeling in furthering our understanding of Novichok nerve agents and their many structural variants. The combination of computational methodologies and QSAR techniques has greatly improved our ability to predict toxicological features, unravel binding mechanisms, and prioritize chemicals for further study. The findings of these studies offer significant promise for strengthening global security measures against this growing class of chemical warfare agents.