Determination of the key chemical reaction pathways in cold atmospheric plasmas (CAPs) is of great importance not only for understanding the spatiotemporal evolutions of the key plasma parameters during discharges but also for improving the plasma materials processing qualities. In this paper, a novel chemical reaction reduction method (CRRM) is proposed by using the global fluid model coupled with the genetic algorithm and the dynamic programming technique. With the aid of this newly developed CRRM, the key chemical reaction pathways can be automatically screened with a high computational efficiency under a pre-set critical calculation accuracy for the atmospheric pure helium and helium–nitrogen glow discharge plasmas. By comparing the calculated key plasma parameters, e.g., the species number densities, electron temperatures, voltage–current characteristics, based on the simplified models and their corresponding full models with those of the experimentally measured data, the reliability of the CRRM itself and the established key chemical reaction database for the atmospheric pure helium and helium–nitrogen CAPs are validated. This research also provides a general method for screening the key chemical reaction pathways for various low-temperature plasma sources.

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