In this work, the uranyl-curcumin metal–organic framework (MOF) samples were synthesized using ultrasound, reflux, hydrothermal and ultrasound assisted reflux techniques. Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, scanning electron microscopy, transmission electron microscopy, and N2 adsorption/desorption isotherm were used to identify and investigate the properties of the samples. The results showed that the synthesized products by ultrasound methods shows excellent properties than the other methods and had a significant porosity of 2.74 nm with the surface area of 42.66 m2/g. In this method, the size of particles is in the range of 40–90 nm, and the samples had a spherical morphology by uniform distribution without any agglomeration. In the second part of this study, the 2k−1 factorial method was used to evaluate the effects of several parameters (pH, contact time, phenol red concentration and photocatalyst content) on the photocatalytic activity of the uranyl-MOF with curcumin ligands in the degradation of phenol red from aqueous samples. The results showed that in optimal conditions (pH 8.04, contact time: 11 min, phenol red concentration: 0.11 mg/L, and amount of MOF: 18.00 mg), more than 99% of the phenol red could be degraded.