This paper describes, for the first time, the application of an Elastodynamic Boundary Element Method (BEM) in Laplace Domain for the Structural Health Monitoring (SHM) of poly-crystalline materials. The study focuses on Ultrasonic Guided Wave (UGW) propagation and investigates the wave–material interactions at micro-scale. The study aims to investigate the interaction of UGWs with assessing micro-structural features such as grain size, morphology, degradation, and flaws. Numerical simulations of the most common micro-structural features demonstrate the accuracy and validity of the proposed method. Particular attention is paid to the study of porosity and its influence on material macro-properties. Different crystal morphologies such as cubic, rhombic, and truncated octahedral are considered. The detection of voids based on the changes in the amplitude and Time of Arrival (ToA) of the backscattered signal is investigated. The study also considers inter-granular cracks, which cause laceration, and examines flaw position/orientation, length, and distance from a specific reference. Furthermore, a framework is proposed for generating Probability of Detection (PoD) curves using numerical simulations. Experimental tests in pristine conditions are shown to be in good agreement with the numerical simulations in terms of ToA, signal amplitude, and wave velocity. The numerical simulations provide insights into wave propagation and wave–material interactions, including different types of defects at the micro-scale. Overall, the BEM and UGW methods are shown to be effective tools for better understanding micro-structural features and their influence on the macro-structural properties of poly-crystalline materials.