[en] Highlights: • 3000 μm² defect-free HCP domain was successfully synthesized. • Relative humidity (RH) as well as the first rotational speed (v_a) of the dual-speed procedure was identified as the quality-control parameters in spin coating. • 23% RH and v_a = 1000 rpm were identified as the optimistic spin coating processing parameters for SiO₂ HCP monolayer. • Statistical experimental design was demonstrated as one efficient strategy for multi-factor processing optimization. - Abstract: A large-area hexagonal packed monolayer of silica spheres with consistent defect-free domains of a size larger than 3000 μm² was prepared by spin coating on glass substrates with the assistance of experimental design and statistical analysis. The ratio of the defect-free monolayer area to the square of sphere diameter is nearly two times of the previously reported maximum values. Several parameters involved in the spin coating systems were investigated. The results indicated that the relative humidity and the rotational speed of the first step of the spin coating had the most important impact on the ordering degree of the prepared monolayer. Furthermore, the ordering degree of the obtained monolayer increased with a decreased relative humidity. In addition, it reached an optimal value when the first rotational speed during spin coating reached a value of 1000 rpm. From this study, it can be concluded that statistical experimental design is an efficient strategy, especially for multi-factor phenomenon studies