A series of new mesoporous silica (MS) sorbents were developed by functionalizing a large-pore 2-D hexagonal MS material, MSU-H, with amidoxime, imide dioxime, phosphonate, and carboxylate functional groups, and characterized by nitrogen adsorption, ζ-potential, infrared spectroscopy, and thermogravimetric analysis. These MS materials have a grafting density of 0.75 to 1.38 mmol/g, and exhibit BET surface areas of 186–526 m2/g and average pore sizes of 3.8–7.8 nm. The uranyl sorption by the functionalized MS sorbents was investigated in basic water and artificial seawater at pH = 8.3 ± 0.1. The MS materials exhibited a high U sorption capacity in water (>40 μg U/mg sorbent) with Langmuir isotherms suggesting a saturation U sorption capacity of 185.2 μg U/mg sorbent for the phosphonic acid-modified MS material (MSPh-III). The U sorption capacity in artificial seawater was reduced to 12.1 μg U/mg sorbent for MSPh-III. Langmuir isotherms indicated a saturation sorption capacity of 66.7 μg U/mg sorbent for MSPh-III, which also had the greatest binding affinity for U of all sorbents tested, followed by the imide dioxime-functionalized material MSCA-I. Kinetics studies show rapid uranyl sorption and equilibration in less than 40 min. The U was quantitatively eluted from the MS sorbents by washing with strong acid (>0.1 M HCl). This work represents the first comprehensive study of organo-functionalized MS materials for U extraction, and shows that phosphonic acid- and imide dioxime-functionalized MS materials provide excellent platforms for developing novel sorbents for efficient U extraction from seawater.