This study aimed to fabricate mucoadhesive gastroretentive microspheres of pregabalin and evaluate the performance of the mucoadhesive microsphere formulations (PMF1 to PMF6) focusing on their percentage yield, drug loading & entrapment efficiency, drug release profiles, mucoadhesive properties, particle characteristics, and fitting to mathematical models. The in-vitro drug release tests revealed that PMF6 had the most controlled and sustained release, reaching 92.32% cumulative release over 12 hours, making it ideal for extended therapeutic effects. Mucoadhesion tests showed that PMF6 retained the highest adhesion at 10 hours, indicating superior mucoadhesive properties. Particle size analysis confirmed that PMF6 had an average size of 340 μm, contributing to its consistent performance. Additionally, PMF6 demonstrated the highest drug loading and entrapment efficiency, ensuring effective encapsulation and delivery of pregabalin. The release data best fit the Korsmeyer–Peppas model for all formulations, suggesting a combination of Fickian diffusion and non-Fickian transport mechanisms. In conclusion, PMF6 emerged as the optimal formulation, combining strong mucoadhesion, high drug entrapment efficiency, and a controlled release profile. These findings highlighted the potential of PMF6 as a promising formulation for sustained drug delivery applications, providing a foundation for further optimization and development in pharmaceutical gastroretentive formulations.