LNG liquefaction is an energy-intensive process. Energy efficiency is the major concern in LNG liquefaction process design and operation. In this paper, a new methodology for LNG liquefaction synthesis targeting energy consumption minimization is presented. It is based on thermodynamic analysis, mathematical programming, and rigorous simulation. The procedure for MINLP (mixed-integer non-linear programming) model development and simplification is described in detail. LINDOGlobal solver in GAMS is employed to solve the MINLP problem and the optimization results are further validated through rigorous simulations. Based on the development, the optimal design and operational conditions for LNG liquefaction process can be simultaneously achieved. A C3MR LNG liquefaction process is employed to demonstrate the efficacy of the developed methodology. Comprehensive thermodynamic analysis is also conducted to give insights of the optimization results. Published by Elsevier Ltd.