This study presents a methodological framework for optimizing “blank” solid lipid nanoparticles (SLNs), focusing on the use of a design of experiments (DOE) approach. Rather than emphasizing the applications of SLNs, the objective is to identify and optimize critical formulation and process parameters—specifically those influencing particle size (PS), polydispersity index (PDI), and zeta potential (ZP)—during early development stages. A non-classical mixed design was applied using AZURAD^® software (version 4.4.1), incorporating a mixture variable for lipid composition (comprising carnauba wax, glyceryl behenate, glyceryl distearate), and two quantitative factors: the percentage of polysorbate 80 (P80) in the P80/sorbitan oleate surfactant system and ultrasound (US) treatment time. The DOE analysis identified P80 concentration as a key parameter, with optimal formulations observed when P80 ranged between 35% and 45%. A fixed P80 ratio of 41% and a US time of 7.5 min enabled precise adjustment of lipid composition. Following a desirability function analysis, an optimized formulation was obtained with a PS of 176.3 ± 2.78 nm, a PDI of 0.268 ± 0.022, and a ZP of −35.5 ± 0.36 mV. These findings validate the relevance of our DOE-based strategy, offering a scalable, cost-effective platform that reduces material use, time, and analytical effort in SLN development.