We report the first quantitative analysis of the structural evolution of a uranyl bearing coordination polymer in response to pressure. The material that is central to this study, (UO2)(O3PCH2CO2H) (1), is constructed from rigid 2D inorganic layers comprising edge sharing UO7 pentagonal bipyramids cross-linked by [PO3(COOH)]2− anions. Strong hydrogen bonding interactions exist between the pendent carboxylic acid groups on adjacent layers. Under pressure, 1 exhibits compressional behaviour primarily in the direction perpendicular to the inorganic layers, which is aided by a reduction in the interlayer distance and shifting of the layers with respect to each other. The bulk modulus for the 2D compound 1 is unexpectedly high [18.1(1)GPa] and is within the range reported for 3D CPs assembled from ZnII cations and inflexible imidazolate anions, and is at the lower end of the range of moduli observed for aluminosilicate zeolites (19–59GPa).