Palladium and palladium/alloy membranes have shown to be an effective technology option for the production of pure hydrogen. In particular, Pd/Au membranes have displayed superior chemical stability and separation performance. However, the lack of industrial operating experience gives rise to technological uncertainties such as the lifetime of the membranes which could potentially prevent the deployment of this new technology option. In light of the above recognition, the primary aim of the present research work is to combine long-term H2 membrane permeance and He leak characterization tests (cumulative testing over 2.2 years) conducted to estimate the lifetime of composite asymmetric Pd/Au membranes at different thicknesses with a comprehensive economic performance assessment framework in the presence of inherent trade-offs between permeance, thickness, and membrane lifetime. The experimental results are depicted in terms of the produced H2 purity and flux at different testing times and various membrane thickness values. Using these experimental results, the lifetime of the membranes is estimated and integrated into the proposed economic assessment framework. The economic evaluation framework for H2 separation units is structured in a way that explicitly recognizes various uncertainty sources via Monte Carlo simulation techniques and assesses economic performance based on metrics such as fixed capital investment (FCI), total capital investment (TCI), total product cost (TPC), and the levelized H2 cost (LC). It is shown that the expected values of the derived FCI/TCI and LC profiles increase as the Pd layer thickness increases while the TPC profile decreases with higher Pd layer thicknesses. Finally, tornado diagrams for the LC are generated to characterize comparatively the importance of H2 permeance and membrane lifetime on the membrane system’s economic performance profile.