High-Efficiency Particulate Air (HEPA) filtration plays a crucial role in maintaining air quality in critical environments such as lean rooms, hospitals, and nuclear facilities. The point of this study is to look into how well nuclear-grade HEPA filters work and behave by looking at the main ways they catch particles using two modeling methods to figure out how well the filters work overall. This study encompasses particles with diameters ranging from 0.05 to 5.00 µm and a density of 1500 kg/m³. The current study systematically examined key parameters such as particle size, fiber diameter, and filtration velocity, which revealed their significant influence on the HEPA filter efficiency. Notably, the most penetrating particle size (MPPS) is identified within the expected range of 0.1–0.3 µm for both approaches. A critical threshold in fiber diameter is discovered when it exceeds 0.85 µm, resulting in a substantial shift in particle penetration and overall collection efficiency. This study also explored the impact of filtration velocity on filter performance, demonstrating increasing deviations as velocity rises, following a polynomial trend. The current study also rigorously validated the model predictions against experimental data from uranine particle filtration tests, confirming the model’s accuracy and applicability. These findings provide essential insights for optimizing the design and operation of nuclear HEPA filters, emphasizing the necessity of considering the particle size, fiber diameter, and filtration velocity. Both modeling approaches exhibit a negligible 0.04% deviation in the MPPS efficiency, which increases polynomially with the filtration velocity. Importantly, both approaches consistently identified the same MPPS regardless of the filtration velocity. Additionally, the model reinforces the substantial impact of fiber size on filter efficiency. A comprehensive comparison with the experimental data yielded closely aligned results with a maximum deviation of 1.14%. This validation strengthens the model’s ability to elucidate the underlying physical phenomena governing the influence of filtration velocity on efficiency, making it a valuable tool in nuclear HEPA filter research and development.