Background/Objectives: Cancer classification using microarray datasets presents a significant challenge due to their extremely high dimensionality. This complexity necessitates advanced optimization methods for effective gene selection. Methods: This study introduces and evaluates the Nuclear Reaction Optimization (NRO)—drawing inspiration from nuclear fission and fusion—for identifying informative gene subsets in six benchmark cancer microarray datasets. Employed as a standalone approach without prior dimensionality reduction, NRO was assessed using both Support Vector Machine (SVM) and k-Nearest Neighbors (k-NN). Leave-One-Out Cross-Validation (LOOCV) was used to rigorously evaluate classification accuracy and the relevance of the selected genes. Results: Experimental results show that NRO achieved high classification accuracy, particularly when used with SVM. In select datasets, it outperformed several state-of-the-art optimization algorithms. However, due to the absence of additional dimensionality reduction techniques, the number of selected genes remains relatively high. Comparative analysis with Harris Hawks Optimization (HHO), Artificial Bee Colony (ABC), Particle Swarm Optimization (PSO), and Firefly Algorithm (FFA) shows that while NRO delivers competitive performance, it does not consistently outperform all methods across datasets. Conclusions: The study concludes that NRO is a promising gene selection approach, particularly effective in certain datasets, and suggests that future work should explore hybrid models and feature reduction techniques to further enhance its accuracy and efficiency.