A study of the mechanical behavior of self-compacting concrete mixtures under sand replacement (as fine aggregate) by iron slag (residue from industrial machining) from 0.0% to 50.0% of mass, variations of water/cementitious material ratio between 0.3 and 0.5 and nano SiO2 incorporation between 0.0% and 2.0% by mass of cementitious materials is presented. Fresh state tests of slump flow were performed, and the main rheological parameters: static yield stress and plastic viscosity were determined from a rheometer. For the hardened state, compressive strength tests were performed. The study of iron slag incorporation and water/cementitious materials ratio variation was developed based on a statistical methodology of central composite design from axial points based on a 2k factorial with central points, besides a posterior analysis of variance and Tukey’s multiple comparison tests. The optimization of these variables was developed using response surface methodology on 7 days compressive strength results, from the statistical design, besides the posterior determination of nano SiO2 effects on the optimized proportions. Among the most relevant results regarding the presence of iron slag, an increase in the early age compressive strength was found, with the optimized mixture strength being more than 100% higher than mixtures without iron slag at 7 days of curing. Regarding the effect of nano SiO2 addition to the optimized mixture, a detriment of the rheological parameters and a consequent reduction of the workability were the most remarkable findings. With the obtained results, iron slag proves to be a feasible sand replacement in self-compacting concrete mixtures.