A straightforward, accurate, and precise approach was created to estimate the amounts of Rilpivirine and Cabotegravir in pharmaceutical dosage form and bulk. Using the central composite model in Quality by Design, Design Expert software 11.0.0 version, chromatographic conditions were optimised. HSS100 x 2.1 mm, 2 m column was used to run the chromatogram. The mobile phase, which included 0.01N phosphate buffer, acetonitrile was injected through the column at a ratio of 55 : 45 (%v/v) was forced through the column at a 0.31 ml/min flow rate. A constant 30°C temperature was maintained. The chosen optimised wavelength was ACQUITYT UV 260.0 nm. The retention times for Rilpivirine and Cabotegravir were determined to be 1.109 and 0.899 minutes, respectively. The percentage RSD for both substances was found to be 1.5 and 0.8. The recovery rates were 100.23 for Rilpivirine and 99.77% for Cabotegravir. Regression equations for both Cabotegravir and Rilpivirine yielded LOD and LOQ values of 0.32, 0.98, 0.67, and 2.04, respectively. The equation for Cabotegravir is y = 3108.8x + 661.44, whereas that for Rilpivirine is = 5694.3x + 1309.5. The method that was created was easy to use and cost-effective, making it suitable for routine quality control testing in industries. Both the retention times and the run time were reduced.