Mebeverine (MBV) is a clinically approved antispasmodic agent indicated for irritable bowel syndrome (IBS) that functions via direct calcium channel inhibition in gastrointestinal smooth muscle, alleviating spasmodic pain without central anticholinergic effects. Optimal oral delivery mandates protection from gastric acidity (pH ~1.5–3.0) and targeted release in the small intestine (pH ~6.0–7.4) for prompt onset and sustained action. Here, we report a comparative evaluation of tartaric acid–iron(III) metal–organic frameworks (TF-MOFs) functionalized with globulin (TF-GLB) or human serum albumin (TF-HSA), loaded with MBV. TF-GLB-MBV released a higher amount of MBV at 7.4 and 9.0, suggesting unsuitability for neutral and basic environments with a concentration of 2.06 mg (12.73 %) and 3.67 mg (22.69 %) at first 15 min, respectively. For TF-HSA-MBV, the maximum MBV release amounts were 3.58 mg (5.22 %) and 0.9 mg (21.20 %), respectively. This comparative kinetic modeling study reveals that TF-HSA-MBV performs optimally in acidic and alkaline environments, following Higuchi diffusion-based release. Meanwhile, TF-GLB-MBV is more suitable for mildly acidic pH, exhibiting Case II transport, suggesting erosion- or swelling-controlled release—ideal for upper intestinal targeting. However, neither formulation performed optimally at physiological pH (7.4), which may require further formulation optimization. These findings support TF-GLB as a promising oral delivery system for IBS.