A simple approach for the formation of 2-oxo-4-phenylbutanoic acid (OPBA), which might find important use as substrate for production of angiotensin-converting enzyme (ACE) inhibitor drug precursor, was studied. With the appropriate choice of solvent and base, it was possible to produce pure OPBA in good yields. In this study, optimization of OPBA synthesis was investigated. Response surface methodology (RSM) and 4-factor central-composite rotatable design (CCRD) were employed to evaluate the effects of synthesis parameters, such as reaction temperature (40–70°C), reaction time (5–13h), choice of solvent (dried tetrahydrofuran or diglyme) and base (sodium methoxide or sodium hydride) on product yield. On the basis of numerical optimization, the optimum conditions for synthesis were: reaction time 6h, reaction temperature 65°C, using dried tetrahydrofuran as solvent and sodium methoxide as the base. The yield obtained was 98%. Comparison of predicted and experimental values revealed good correspondence, implying that empirical models derived from RSM can be used to adequately describe the relationship between the factors and response in OPBA synthesis.