Achieving a certain predicted quality with intended and predetermined parameters is known as quality by design (QbD). Due to the emphasis on risk assessment and management compared to a traditional or conventional approach, a quality-by-design approach to method development may result in a more robust or rugged method. Understanding dependent variables, different variables and their interaction effects by the desired set of trials on the responses that need to be studied is a crucial part of the QbD. The development and validation of a risk-based HPLC technique for Remdesivir in pharmaceutical dose form are described in the current work. Remdesivir technique development with the mobile phase methanol and acetonitrile combined to water [(methanol + ACN): water] has not been reported in the literature review. Using this mobile phase, the developed method will also be economical. Also, there exists no report in the literature survey on method development of Remdesivir by QbD approach. Results: An efficient experimental design based on 3 level factorial design of three key components of the RPHPLC method (mobile phase composition and flow rate) is presented. The chromatographic conditions were optimized with the Design Expert software 10.0 version, i.e., Acclaim TM Mixed-Mode WCX-1 column C18 (150mm × 4.6 mm) 120 Å, mobile phase used methanol and acetonitrile in combination (60:40) to water (60:40, v/v), and the flow rate was 0.8 ml/min with retention time 4.18 min. The developed method was found to be linear with r2 = 0.996 for range of 10–30 μg/ml at 243 nm detection wavelength. The system suitability test parameters, tailing factor and theoretical plates, were found to be 1.05 and 7701 respectively. The % RSD for method precision and interday precision was found to be 1.00 and 1.26 respectively. The robustness values were less than 2%. The method validation parameters were in the prescribed limit as per ICH guidelines. Conclusion: With the aid of the Design Expert 10.0 edition, the 3-level factorial design experimental design describes the interactions of mobile phase composition and flow rate at three different levels and the responses to be examined were retention time, tailing factor, and theoretical plates. Here, the elements that affect chromatographic separation are more understood, and the created HPLC method's capacity to achieve its goals is more confidently assessed. The QbD methodology was used to construct analytical methods and improve knowledge of method variables at various stages.