The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past years. Increasingly employed to improve the delivery efficiency and therapeutic efficacy of RNA are lipid nanoparticles (LNPs). Many of the various critical formulation parameters can affect the quality attributes and effectiveness of these nano-formulations. Therefore, the systematic drug development approach (QbD) and multivariate design and statistical analysis (DOE) can be very helpful and recommended for the optimization of the composition and production of RNA–LNPs. This review addresses the concepts and applications of QbD and/or DOE for the development of lipid nanoparticles for the delivery of different types of RNA, reporting examples published in the ten recent years presenting the latest trends and regulatory requirements as well as the modern mathematical and statistical design methods. As the topic explored in this review is a novel approach, the full QbD has been described in only a few papers, and a few refer only to some aspects of QbD. In contrast, the DOE approach has been used in most of the optimization works. Different approaches and innovations in DOE have been observed. Traditional statistical tests and modeling (ANOVA, regression analysis) are slowly being replaced by artificial intelligence and machine learning methods.