Metal-organic frameworks-5 (MOF-5) were explored for enhancement of the solubility and dissolution of the drug niclosamide (NIC). MOF-5 was synthesized by solvothermal method and NIC was loaded into it (NIC@MOF-5). Characterization was done using field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller surface area (BET-SA), and energy-dispersive X-ray spectroscopy (EDS). The effect of loading time on the percentages of entrapment efficiency (%EE) and loading capacity (%LC) were studied. The effect of incorporation into MOF-5 on saturated solubility and dissolution profiles of NIC was investigated in three different media: acidic buffer solution (ABS) pH 1.2, deionized water (DW) pH 6.2, and phosphate buffer solution (PBS) pH 7.4. The results showed that the solubility of NIC was significantly improved upon incorporation into MOF-5 in all media. In ABS pH 1.2, it was improved by 3.4 times (10.63 ± 1.04 µg/ml versus 3.17 ± 0.55 µg/ml). In DW pH 6.2, it was improved by 4.7 times (60.37 ± 4.74 µg/ml versus 12.83 ± 1.76 µg/ml). The biggest improvement was in PBS pH 7.4 by 6.1 times (209.85 ± 9.77 µg/ml versus 34.5 ± 1.66 µg/ml. For dissolution, the cumulative release at the end of point was significantly higher for NIC@MOF-5 in all three media: 51.20% ± 6.52% versus 10.77% ± 1.78% in ABS pH 1.2, 54.09% ± 1.81% versus 12.44% ± 0.57% in DW pH 6.2, and 84.87% ± 9.99% versus 19.48% ± 1.82% in PBS pH 7.4. Characterization confirmed the identity of NIC and MOF-5 as well as loading of NIC into MOF-5 without significant interactions. It is, therefore, concluded that MOF-5 is a feasible formulation approach to improve the solubility of and dissolution of NIC in either acidic media, water, or basic media.