This study introduces an innovative approach to alloy design by experimentally validating the semi-empirical concept of Griessen and Driessen, which predicts the hydrogen affinity of solid solutions. The work focuses on designing and synthesizing four equiatomic high-entropy alloys (HEAs) with compositions tailored to exhibit highly endothermic enthalpies of solution and formation, resulting in resistance to hydrogen absorption. Unlike conventional studies that prioritize hydrogen storage capacity, this research uniquely targets alloys optimized for minimal hydrogen interaction, addressing critical needs in hydrogen storage and transportation technologies prone to hydrogen embrittlement. Experimental results confirm the negligible hydrogen absorption of these alloys, with a maximum of 0.23 wt.% (H/M = 0.13) at 2 MPa and 175 °C. This study not only demonstrates the applicability of a theoretical model to guide alloy design but also highlights the potential of these materials for low-pressure hydrogen storage systems, where mechanical integrity and resistance to hydrogen degradation are paramount. The findings bridge the gap between theoretical predictions and practical applications, offering a novel perspective on alloy development for hydrogen-related technologies.