The research aimed to investigate the mucoadhesive properties of Aloe vera leaf mucilage (AVLM) when combined with Clarithromycin (CMN) to create mucoadhesive microspheres. The study involved the preparation of nine batches of CMN mucoadhesive microspheres using carbopol 934P (C-934P) and varying amounts of AVLM. To analyze the effects of AVLM and C-934P levels on particle size (PS) and swelling index (SI) as response variables, a central composite design was employed with design expert software. The results indicated that the PS of the microspheres ranged from 35.2±0.3 to 48.1±0.6μm, with batch B-1 having the smallest PS and B-8 showing the largest size. The PS was determined using the formula: +49.37+0.3500A+1.73B-0.8750AB-0.2500A²-8.10B², where A represents the AVLM level and B represents the C-934P level. On the other hand, the SI of the microspheres varied from 56.8 to 61 and increased with higher polymer content. The formula for the SI was: +59.10+0.2500A+1.90B-0.1500AB+0.2500A²-0.3000B². The study found that AVLM levels significantly influenced the PS and SI of the microspheres. Moreover, the researchers observed a controlled release of CMN from the microspheres, with satisfactory entrapment efficacy, mucoadhesion, and drug contents, meeting various constraints. Additionally, the microspheres demonstrated potential for targeted drug delivery to the stomach due to C-934P, and the presence of AVLM further enhanced this effect. Scanning electron microscopy images confirmed that the microspheres had a spherical shape with a relatively smooth surface. Overall, the study established the potential of AVLM-based mucoadhesive microspheres for controlled drug delivery, with promising results using CMN as a model drug.