LNG ISO tank containers are a solution for bulk liquefied natural gas (LNG) delivery to the outer islands of Indonesia that are not connected to the gas pipeline network. The design of an ISO tank frame must consider two critical parameters, strength/rigidity and weight saving, which affect the operational performance of the distribution process. The current investigation aims to numerically optimize the design of the structural frame of a 40 ft LNG ISO tank for a mini LNG carrier operation using a topology optimization framework. Two design solutions are used in the topology optimization framework: reducing the strain energy and mass retained. Mass retained was selected as the objective function to be minimized, which was assumed to be 60–80%. The proposed frame design is tested using three operational loading scenarios, including racking, lifting, and stacking tests based on the ISO 1496 standard. The convergence mesh tests were initially evaluated to obtain the appropriate mesh density in the finite element analysis (FEA). The simulation findings show that the topology optimization method of the frame design resulted in an improved design, with an increase in the strength-to-weight saving ratio. A promising result from the optimization scenario demonstrates weight savings of about 18.4–37.3%, with experienced stress below the limit criteria. It is found that decreasing mass retained causes a significant stress increase in the structural frame and ISO corner castings, especially in the stacking load. The critical recommendation in the frame design of the LNG ISO tank can be improved by eliminating the saddle support and bottom frame and increasing the thickness of the vertical frame.