A study had been conducted on the optimization and validation of high-performance liquid chromatography (HPLC) method for quantitative analysis of whitening agents namely hydroquinone (HQ) and retinoic acid (RA) in cream cosmetics. Using experimental design of response surface method, the optimal condition of mobile phase resulted of methanol:water:glacial acetic acid (88:12:0.4 v/v/v), with a flow rate of 1.2 mL/minute. The separation of HQ and RA was achieved using column of STAR LP Purospher® stationary phase RP-18 end-capped (250 × 4.6 mm, 5 μm) at a temperature of 45°C. Detection was performed using photodiode array (PDA), set at wavelength 310 nm. HPLC-PDA was validated by assessing several parameters, namely selectivity, linearity, accuracy, precision, detection limit, quantitation limit, and robustness. The validation results showed that the analytical method was selective, linear with a correlation coefficient (r) of ≥0.9998, precise with the relative standard deviation (RSD) of inter-day precision of ≤3.44%, accurate with recovery percentage of HQ and RA of 100.00% and 99.67%, respectively. The detection limits of HQ and RA were of 0.44 and 0.47 mg/g, sample respectively; while the limits of quantitation of HQ and RA were of 5.09 and 1.71 mg/g samples, respectively. The developed method was successfully used for analysis of HQ and RA in commercial cream samples.