Abstract To obtain high yield and high concentration glucose from corncob residues (CRs), tetrahydrofuran (THF) + H2O co-solvent pretreatment was employed. The pretreatment parameters were firstly optimized by Box-Behnken Design of response surface method, and the maximum glucose yield (498.2 mg/g CRs) was obtained via enzymatic hydrolysis after pretreated under optimized conditions (53.7% THF concentration, 202.3 °C, 1.05 h). Then, the pretreated CRs under optimized conditions (optimized-CRs) were enzymatically hydrolyzed at high solid loading (15%–20%) and low enzyme input (5–8 FPU/g cellulose). The high concentration glucose production (128.6 mg/mL) was obtained from optimized-CRs after enzymatic hydrolysis at 20% solid loading with 10 FPU/g cellulose for 72 h, and then showed potential for reduction of enzyme input. Finally, the interactions between the 9 substrate-related factors and cellulose conversion were analyzed through correlation analysis, and found that Klason lignin remained in the cellulose-rich fractions and pseudo lignin condensed on the surface of the recovered substrate were the predominant inhibitors for enzymatic hydrolysis.