This study examined the effect of cell-wall-degrading enzymes added to temper water on wheat milling performance and flour quality. An enzyme cocktail consisting of cellulase, xylanase, and pectinase and five independent variables (enzyme concentration, incubation time, incubation temperature, tempered wheat moisture content, and tempering water pH) were manipulated in a response surface methodology (RSM) central composite design. A single pure cultivar of hard red winter wheat was tempered under defined conditions and milled on a Ross experimental laboratory mill. Some treatment combinations affected flour yield from the break rolls more than that from the reduction rolls. However, a maximum for flour yield was not found in the range of parameters studied. Though treatments did not affect the optimum water absorption for breadmaking, enzyme-treated flours produced dough exhibiting shorter mixing times and slack and sticky textures compared with the control. Regardless of differences in mixing times, specific loaf volumes were not significantly different among treatments. Crumb firmness of bread baked with flour milled from enzyme-treated wheat was comparable to the control after 1 day but became firmer during storage up to 5 days.