Hydrogen (H2) liquefaction process is one of the complex processes because of the highly non-linear interaction between design variables and objective function. Finding a feasible design for such a complex process is challenging. Knowledge of refrigerant selection, composition, cycle temperatures, and compression ratio is essential in finding this feasible design. This study presents a simple, yet efficient approach inspired by process knowledge, known as knowledge-based optimization (KBO), to selecting an optimal mixed refrigerant (MR) composition and studying the effect of each refrigerant on the performance of the H2 liquefaction process. The infeasible design shows approach temperature (i.e., MITA) values as −33.5 °C, −4.0 °C, and −11.65 °C. The design variables' values are adjusted based on the KBO approach to keep the MITA value in the range of 1–2 °C. The share of each MR component in optimal case is 17% C1, 5% C2, 70% C3, 8% N2 in precooling, 9% C1, 80% N2, 11% H2 in cooling and 85% H2, 15% He in liquefaction cycle. Further, the KBO approach guides in selecting the lower and upper limit of each refrigerant based on their impact inside heat exchangers. Additionally, the heat flow behavior of H2 streams is analyzed for adiabatic and isothermal ortho-to-para reactors. This study will help process engineers and engineering practitioners to develop an energy-efficient and cost-effective initial design for the H2 liquefaction process.