The present study investigated the effect of independent variables, i.e., barley flour (30 to 50%), water content in liquid whey (83.3 to 93.3%), and dough resting time (90 to 150 min), on liquid whey incorporated wheat-barley buns (LWWBb). To optimize the independent variables, Response Surface Methodology using Box–Behnken design was applied, and their effect on the overall acceptability score, crude fat (g), total dietary fiber (g), firmness (g), and springiness (g) were observed. The optimized nutritious LWWBb was obtained at barley flour (45.60%), water content in liquid whey (91.70%), and dough resting time (125 min). Comparative analysis of optimized LWWBb (O-LWWBb) and refined wheat flour bun (RWb) were done for physical and nutritional characteristics. The results of comparative analysis revealed that O-LWWBb has 2.95 g/100 g, 51.51 mg/100 g, 158.39 mg/100 g, 1.95 mg/100 g, and 26.96% more fiber, calcium, phosphorus, iron, and antioxidant activity, respectively, as compared to RWb. The study discloses that highly nutritious buns can be developed successfully by utilizing liquid whey and wheat-barley flour.