Expander-based liquefaction processes for the production of Liquified Natural Gas (LNG) have gained attention in recent years. A variety of different expander-based natural gas liquefaction processes have been proposed and are analyzed by different researchers primarily based on their experience. The chosen liquefaction process affects the process energy inputs significantly. The existing approach does not provide any insights into the process synthesis approach to identify the optimal configuration as they primarily rely on the process analysis approach. This work proposes a novel systematic design methodology to determine the minimum specific power consumption of the expander-based natural gas liquefaction process prior to design. The optimal process configuration for work and heat integration is obtained by effectively leveraging principles of multi-stream heat exchanger network design. Application of the proposed method for the production of LNG shows that the expander-based natural gas liquefaction configurations with significantly lower specific power consumption can be obtained as compared to the existing configurations in the literature.