Introduction: Developing and optimizing isocratic HPLC methods is a difficult procedure that requires simultaneous determination of several factors. Objective: To develop a simple, accurate, rapid, and precise chemometric-assisted RP-HPLC method for the simultaneous estimation of Paracetamol (PARA) and Ibuprofen (IBU) in bulk and in pharmaceutical formulation. Methods: The method involves the design of experiment (DOE) approach for the optimization of the mobile phase by keeping in concern about the dependent variables (flow rate, methanol, and pH) and their consequence was perceived over the retention time (Rt) and resolution of drugs. Results: Based on the trial runs, the optimized condition generated by the software was used for the separation of PARA and IBU on Thermo C18 Column (150 mm __ampersandsigntimes; 4.6 mm i.d., 5 __ampersandsignmu;m). The chromatographic separation was achieved by using the optimized mobile phase consisting of methanol and sodium dihydrogen phosphate buffer (88.3: 11.7 % v/v), adjusted to pH 2.5, delivered at a flow rate of 1.2 mL/min and the detection was carried out at 222 nm. The retention time (Rt) was found to be 2.241 minutes for PARA and 3.535 minutes for IBU. The developed method was validated as per ICH guidelines. The calibration curves of PARA and IBU were found to be linear in the range of 6.5-39 __ampersandsignmu;g/mL and 8-48 __ampersandsignmu;g/mL, respectively. The recoveries for the two compounds were close to 100% at various levels. Conclusion: This method can be successfully applied for routine quality control analysis of these drugs in bulk and pharmaceutical formulations.