Research in the field of autonomous Unmanned Aerial Vehicles (UAVs) has significantly advanced in recent years, mainly due to their relevance in a large variety of commercial, industrial, and military applications. However, UAV navigation in GPS-denied environments continues to be a challenging problem that has been tackled in recent research through sensor-based approaches. This paper presents a novel offline, portable, real-time in-door UAV localization technique that relies on macro-feature detection and matching. The proposed system leverages the support of machine learning, traditional computer vision techniques, and pre-existing knowledge of the environment. The main contribution of this work is the real-time creation of a macro-feature description vector from the UAV captured images which are simultaneously matched with an offline pre-existing vector from a Computer-Aided Design (CAD) model. This results in a quick UAV localization within the CAD model. The effectiveness and accuracy of the proposed system were evaluated through simulations and experimental prototype implementation. Final results reveal the algorithm’s low computational burden as well as its ease of deployment in GPS-denied environments.