In the current study, two analytical methods are developed using spectrophotometry and high performance liquid chromatography for the determination of pregabalin in pharmaceutical preparations. Box-Behnken Design model was adopted to ease the optimization process. The visible spectrophotometric method is based on the reaction of potassium ferricyanide and ferric chloride in an acidic medium and measured absorbed at 700 nm. The HPLC method utilizes ammonium formate buffer solution and RP18 base deactivated silica (BDS) column for the quantitative analysis of pregabalin. The calibration plot was found to be linear in the range of 1.5–26.2 and 0.4–17.6 µg/mL for spectrophotometric and HPLC methods. BBD is a powerful statistical experiment design for optimizing reaction conditions that minimize the number of experiments and the cost of the method. Response Surface Methodology (RSM) via Box–Behnken design (BBD) optimized the chromatographic procedure. The Greenness of the methods were also evaluated by considering the Analytical Greenness Metric Approach. Method I attained a score of 0.74, while method II scored 0.59, suggesting an excellent and considerable level of eco-friendliness. Moreover, it is economical, consumes a minimum amount of organic solvent, and has good accuracy and precision.