Crack growth is a pivotal concern in structural engineering, directly impacting structures’ stability, quality, and overall lifespan. This study addresses this challenge by investigating structural optimization strategies to mitigate fatigue crack growth (FCG) by strategically incorporating stop-drilled cutouts near the crack tip. The research introduces three optimization problems, focusing on determining the optimal cutout position with a fixed radius, the optimal cutout radius with a fixed position, and the optimal cutout shape with a constant position for the cutout’s center. Experimental assessments are conducted on an edge-cracked AISI 1045 steel plate to evaluate the effectiveness of these optimization strategies in enhancing fatigue life. Employing the Extended Finite Element Method (XFEM) for numerical simulations and Particle Swarm Optimization (PSO) for the optimization process, the findings reveal that strategically positioned cutouts substantially reduce the crack growth rate. Optimal cutout placement significantly improves fatigue life, demonstrating an approximate 287% increase. The analysis affirms the accuracy of the numerical model in predicting fatigue life and crack growth paths, validated through comparison with experimental data. In summary, this research underscores the effectiveness of optimization techniques in mitigating fatigue crack growth, providing valuable insights for structural integrity enhancement in structural mechanics.