Crumb rubber (CR) from scrap tires is used as a partial replacement of fine aggregates in cement paste. This promotes the sustainable development of the environment, economy, and society, as waste tires are non-biodegradable and flammable. They occupy large landfill areas and are breeding grounds for mosquitoes and rodents. Inclusion of CR in mortar leads to several improvements on the mixture properties such as ductility, toughness, and impact resistance. However, it exhibits lower strengths and Modulus of Elasticity (ME). Therefore, to promote the use of mortar containing CR, it is vital to improve its mechanical strength. Past studies proved that nano-silica (NS) improves the strength of concrete due to the physico-chemical effects of NS. This study aims to examine the mechanical properties of crumb rubber mortar containing nano-silica (NS-CRM) and to develop models to predict these properties using Response Surface Methodology (RSM). Two variables were considered, CR as partial replacement to sand by volume (0, 7.5, 15), and NS as partial replacement to cement by weight (0, 2.5, 5). The results demonstrated a significant improvement in the mechanical properties of CRM when incorporating NS, and the models developed using RSM were acceptable with a 2 to 3 variation. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.