Abstract The mixed fluid cascade (MFC) process is considered one of the most promising candidates for producing liquefied natural gas (LNG) at onshore sites, mainly owing to its high capacity and relatively high potential energy efficiency. The MFC process involves three refrigeration cycles for natural gas precooling, liquefaction, and subcooling, making its operation more complex and sensitive. Each refrigeration cycle consists of a different mixed refrigerant, which must be optimized to change feed and ambient conditions to operate efficiently. Any sub-optimal solution can lead to high exergy losses, ultimately reducing the process energy efficiency. Operating optimally is a challenging task, mainly owing to the non-linear interactions between the constrained decision (design) variables and complex thermodynamics involved in MFC refrigeration cycles. In this context, we employ a multivariate Coggins step-up approach to reduce the exergy losses associated with the MFC process. This study reveals that the overall exergy losses can be minimized to 35.91%; resulting in 25.4% overall energy savings compared to sub-optimal MFC processes.