Purpose Pregabalin (LYRICA®) is a centrally acting neuromodulating agent for the management of neuropathic pain and fibromyalgia. Owing to its short half-life, LYRICA® controlled release (CR) tablets have been approved to be administrated once daily. However, the tablets are prepared by a multi-step process using a combination of release-controlling, wetting, pore-forming, and gelling agents. Hence, there is a need to develop a simple cost-effective environment-friendly methodology for the manufacturing of pregabalin extended release (ER) tablets. Methods Quality by design (QbD) was applied for simple manufacturing of pregabalin extended release tablets with comparable efficacy to the reference product LYRICA® CR (82.5 mg) utilizing hydrophilic and lipid components and hot-melt granulation. The design of experiment (DoE) based on Taguchi model was utilized to investigate the effect of combination of various hydrophilic and lipophilic matrices, fillers and compression forces on the release of pregabalin ER tablets. Pre-compression blends were evaluated for micrometrics while tablets were evaluated for drug content, average weight, hardness, friability, thickness, dissolution and release kinetics. A pharmacokinetics study was performed to evaluate the pharmacokinetics profile of the optimized formulation as compared to the reference marketed product. Results Results, analyzed using Minitab software® 18, determined significant and non-significant variables. The lipophilic meltable binder displayed significant effects on the pre-compression blend characters, yet not able to attain an extended release profile for pregabalin. Combination of hydrophilic and lipophilic matrices efficiently developed pregabalin tablets of extended-release pattern. The optimized formulation (composed of 80 mg of stearic acid, 100 mg of Methocel K15M and lactose with compression value of 10 KN) showed a comparable pharmacokinetics profile to the reference drug in terms of AUC (4.12 and 4.78 µg.h/mL, respectively) and Cmax (0.31 and 0.36 µg/mL, respectively) using a pilot-scale bioequivalence study in albino rabbits. Conclusion QbD and DoE can be effectively applied for the design and development of a timesaving and eco-friendly methodology for the preparation of pregabalin ER tablets as an alternative to the marketed product.