This article presents a Model-Based Systems Engineering (MBSE) methodology for the development of a Digital Twin (DT) for an Unmanned Aerial System (UAS) with the ability to demonstrate route selection capability with a Mission Engineering (ME) focus. It reviews the concept of ME and integrates ME with a MBSE framework for the development of the DT. The methodology is demonstrated through a case study where the UAS is deployed for a Last Mile Delivery (LMD) mission in a military context where adversaries are present, and a route optimization module recommends an optimal route to the user based on a variety of inputs including potential damage or destruction of the UAS by adversary action. The optimization module is based on Multiple Attribute Utility Theory (MAUT) which analyzes predefined criteria which the user assessed would enable the successful conduct of the UAS mission. The article demonstrates that the methodology can execute a ME analysis for route selection to support a user’s decision-making process. The discussion section highlights the key MBSE artifacts and also highlights the benefits of the methodology which standardizes the decision-making process thereby reducing the negative impact of human factors which may deviate from the predefined criteria.