Explosions have evolved beyond military applications, now impacting various contexts such as industrial accidents and terrorism, each with unique challenges. In particular, urban infrastructure and critical facilities are increasingly at risk, necessitating advanced protective measures. Touch-off explosions can cause widespread destruction when an explosive directly strikes a target, significantly increasing its destructive potential. Concrete slabs in buildings are especially vulnerable to these forces, as they bear structural loads and maintain overall integrity. Their propensity to fracture under the pressure of such explosions highlights the need for improved structural design and safety protocols. Enhancing their blast resistance is crucial for ensuring occupant safety and preventing progressive collapse. This research evaluates and enhances the blast resilience of concrete slabs by integrating steel wire mesh reinforcement. A baseline analysis of a reference slab reinforced solely with tension steel is validated against experimental data from Zhao et al., establishing a benchmark for further enhancements. The study examines two configurations of steel wire mesh, welded into the upper and lower layers of the slabs with nominal pitches of 15 mm and 10 mm, aiming to optimize blast performance. Using an Eulerian–Lagrangian method combined with finite element analysis in Abaqus, the blast loading is simulated to accurately capture the interaction between the blast wave and the slabs’ structural response. Results show that both mesh configurations reduce deformation, peak stresses, and perforation sizes compared to the standard slab. Additionally, analysis of plastic damage metrics indicates that finer mesh spacing enhances energy absorption and structural integrity under blast conditions. The study also underscores the importance of reinforcement placement, as it directly influences failure patterns and overall slab stability. These findings demonstrate the effectiveness of steel wire mesh reinforcement in mitigating blast damage and strengthening concrete structures in hazardous environments. Future research can explore hybrid reinforcement strategies and material innovations to further improve blast resistance in critical infrastructure.