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This work established an integrated utilization of dairy whey in β-galactosidase production from <i>Lactobacillus bulgaricus</i> and prebiotics synthesis by the probiotic enzyme. A cost-effective whey-based medium was newly developed for culturing <i>Lactobacillus bulgaricus</i> to produce β-galactosidase. The medium was optimized through response surface methodology (RSM) involving a series of statistical designs, such as the Plackett–Burman design, steepest ascent experiment, and central composite design. Under the optimized medium, the β-galactosidase activity of <i>L. bulgaricus</i> reached 2034 U/L, which was twice that produced from the traditional MRS medium. The cells of <i>L. bulgaricus</i> harvested from the whey-based medium were subsequently treated with lysozyme. The resulting crude enzyme was used as an efficient catalyst, which catalyzed the synthesis of the prebiotic galacto-oligosaccharides (GOS) in a high yield of 44.7% by using whey (200 g/L) as the substrate. The sugar mixture was further purified by activated charcoal adsorption, thereby yielding a high-purity level of 77.6% GOS.