To investigate the effect of high solid concentrations (w/w) on the enzymatic hydrolysis of yeast cells, yeast cells were hydrolyzed by papain and Alcalase at 18% and 28% solid concentrations (w/w), respectively. High solid concentrations resulted in high protein recovery, degree of hydrolysis (DH) and contents of reducing sugar and 5′-nucleotides (5′-GMP, 5′-IMP), which indicated a positive effect on the release of yeast intracellular substances. High-performance liquid chromatography (HPLC) analysis showed negligible difference in the molecular mass distribution of peptides. The micromorphology of the hydrolysed yeast cells was studied by transmission electron microscopy (TEM). Result demonstrated that high solid concentrations accelerated the plasmolysis, deformation and lysis of yeast cells. Similarly, addition of NaCl or commercial yeast extract to the yeast cell suspension (18% w/w) improved the DH. Therefore, high concentrations of NaCl or yeast cell hydrolysates in solutions with high solid concentrations could damage the yeast cell membrane, leading to effective contact between the enzyme and the substrate and consequent increase in the hydrolysis efficiency. Nevertheless, the hydrolysis mechanism remains unknown and must be further investigated.