Monacolin K is one of the bioactive substances produced by Monascus ruber during fermentation. The multi-factors and their interactions on the effect of solid-state fermentation of Monascus for high yield of monacolin K were attractive to industrial production. A detailed study of 7 single-factor experiments and a series of experiments with Plackette-Burman and Box-Benhnken design, data fitting and modeling, and analyzing the visual 3D response surface plots for investigation of the key factors for Monacolin K production. The results showed that initial moisture (50 ~ 55%) and bran content (4.5 ~ 5.5%) as the key factors of transport for nutrients and oxygen during the solid-state fermentation (SSF) process of Monascus. Under the optimal conditions, a temperature shifting of the SSF with a higher Monacolin K yield of 14.53 ± 0.16 mg·g− 1 compared with the content of monacolin K in the commercially available functional red yeast rice of 8 mg g− 1.