Contents of selected volatile esters and fusel alcohols and their relation to the sensory quality of a bottom-fermented lager beer fermented under high-gravity conditions (15.5 °P) were analyzed using response surface methodology (RSM, Box−Behnken design). The influence of various pitching rates (6−10 mln cells/mL), aeration levels (8−12 mgO2/mL), times (4.5−13.5 h) of filling CCTs (cylindroconical fermentation tanks; 3850 hL), and fermentation temperatures (8.5−11.5 °C) on the contents of selected esters, as well as on concentrations of amyl alcohols and on the sum of higher alcohols in beer, was determined in a commercial brewery fermentation plant. Beers produced throughout the experiments met or exceeded all criteria established for a commercial, marketed beer. Statistical analyses of the results revealed that within the studied ranges of process parameters, models with diversified significance described the concentrations of volatiles in beer. The multiple response optimization procedure analyses showed that the values of process parameters that minimized higher alcohols in beer (97.9 mg/L) and maximized its ethyl acetate (22.0 mg/L) and isoamyl acetate (2.09 mg/L) contents, as well as maximized the sensory quality of beer, (66.4 pts) were the following: Pitching rate 10 mln cells per mL; fermentation temperature 11.5 °C; aeration level 8.8 mg/L; and CCT filling time 4.5 h.