<p>Two simple, rapid, cost-effective, precise, and accurate UV spectrophotometric methods have been developed for the estimation of Clevidipine butyrate, a dihydropyridine calcium channel blocker and antihypertensive agent, using an analytical quality by design approach. The characterization of Clevidipine butyrate was performed by melting point, differential scanning calorimetry, and FT-IR techniques. Using the analytical quality-by-design approach, the critical method variables selected were scanning speed and sampling interval via Central Composite Design, which demonstrated the work's resilience and optimised methodology. A method for UV spectroscopy was developed using two methods — method I, based on the maxima absorption method of zero-order spectrophotometrics with λ_max of 238 and 362 nm, and method II, based on the zero-order area under curve method, wavelength range 233–243 and 353–371 nm, respectively. Both the developed methods were subjected to validation as per the guidelines set by the ICH. The methods showed good linearity in the concentration, ranging from 2 to 12 μg/mL, while the % Recovery of the developed methods was in a range of 98.41–100%. The methods showed good sensitivity and appropriate precision with an RSD less than 2%, and the methods were applied for determination of the Clevidipine synthetic mixture. The developed method's greenness profile was evaluated and compared using the AGREE and MoGAPI tools and were found to be in compliance with twelve principles of green analytical chemistry.</p>