Silica nanoparticles (SNPs) are one of the most researched drug/gene delivery platforms due to their easy and cheap production. Their toxicity depends on the nanoparticle characteristics like particle size or shape. It is well known that the smaller nanoparticles have a better cellular uptake potential. For this reason, in this study, we synthesized SNPs with a particle size of around 100 nm via an experimental design method that combines Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS) with Taguchi design to optimize more than one response. After the optimization, average particle size, particle size distribution, zeta potential, and particle morphology of validated SNPs were analyzed. The cytotoxicity studies were performed on fibroblast cells (L929) for 48 and 72 hours. Results show that obtained nanoparticles were spherical-shaped with a size of around 100 nm and had good biocompatibility.