Abstract The present studies describe the systematic development and validation of a simple, rapid, sensitive and cost-effective reversed-phase high-performance liquid chromatographic bioanalytical method for the estimation of valsartan in rat plasma employing analytical quality by design (AQbD) principles quality risk management was applied for identifying the critical method parameters (CMPs) and subsequently method optimization was performed employing Box–Behnken design by selecting mobile phase pH, flow rate and % organic modifier as the CMPs and evaluated for critical analytical attributes (CAAs) such as peak area, retention time, peak tailing and number of theoretical plates. The developed method was then transferred to bioanalysis, where liquid–liquid extraction process was used for separating the drug from rat plasma. The optimization of extraction process was performed with the help of face-centered cubic design by selecting centrifugation speed and centrifugation time as the CMPs for maximizing % recovery, signal-to-noise ratio and purity threshold of the drug peak after extraction as the CAAs. Optimum chromatographic solution was chosen by mathematical and graphical search techniques, and design space was demarcated. Validation studies performed for the developed method indicated linearity ranging between 5 and 100 ng.mL−1, whereas accuracy and precision study showed good percent recovery (99–102%) along with % relative standard deviation within ±2%. Sensitivity evaluation revealed limit of detection and limit of quantification were found to be 0.76 ng.mL−1 and 2.29 ng.mL−1, respectively. In a nutshell, the present work demonstrates significant merits of AQbD approach for holistic process understanding and analytical method development and validation with enhanced robustness and performance.