By using desired and specified requirements, quality by design (QbD) aims to attain a certain predictable quality. Understanding components and the impacts of their interactions through a chosen set of tests is a highly helpful QbD component. The current work outlines the creation of a thorough science- and risk-based HPLC technique for the analysis of Erlotinib active pharmaceutical ingredient (API) utilizing a quality by design methodology. The three essential elements of the RP-HPLC method—the column, pH, and mobile phase—are systematically explored in this article to create an effective experimental design. The approach was linear as specified. (r (2)=0.999). The results for accuracy, ruggedness, and robustness were all within the prescribed ranges (1% for system precision and 2% for other characteristics). Erlotinib may be routinely analyzed using the suggested approach in quality control labs.