Understanding the reactivity of carbon surfaces is crucial for the development of advanced functional materials. The SW defect is commonly present in carbon materials, but a comprehensive understanding of its effects on the reactivity of carbons is missing. In this study, we systematically investigate the reactivity of graphene surfaces with the Stone-Wales (SW) defect using Density Functional Theory calculations. We explore the atomic adsorption of various elements, including rows 1–3 of the Periodic Table, potassium, calcium, and selected transition metals. Our results demonstrate that the SW defect enhances binding with the studied adsorbates when compared to pristine graphene, with carbon and silicon showing the most significant differences. Additionally, we examine the effects of mechanical deformation on the lattice by constraining the system with the SW defect to the pristine graphene cell. Interestingly, these constraints lead to even stronger binding interactions. Furthermore, for carbon, nitrogen, and oxygen adsorbates, we observe that mechanical deformation triggers the incorporation of adatoms into the carbon bond network, leading to the reorganization of the SW defect structure. This work establishes a foundation for future studies in the defect and strain engineering of graphene, opening avenues for developing advanced materials and catalysts with enhanced reactivity and performance.