We used neutron diffraction with an incident wavelength of 0.7054 Å and both H/D and ⁵⁸Ni/⁶²Ni isotopic substitution to study the interlayer structure of hydrated Ni-exchanged Wyoming montmorillonite powders having 14.9 Å interlayer spacing. We used a double difference method to obtain the g_NiH(r) partial pair correlation function, as well as the complementary pair correlation function, g_NiX(r), which together describe the structure around the Ni²⁺ ion. The hydration structure of the Ni²⁺ hexaaqua ion is found to be very close to that found in aqueous solution. Furthermore, the hydrogen isotope first-order difference gives a weighted sum of partial pair correlation functions, g_Hα(r), related to the intra- and inter-molecular structure around interlayer water hydrogens. These confirm our previous finding for Li-montmorillonite that the interlayer water adopts a liquid-type structure and that the clay surface does not prevent the interlayer water from having a highly hydrogen-bonded configuration. We used reverse Monte Carlo simulations to generate molecular configurations compatible with our first- and second-order difference data. These configurations show a tendency for interlayer water to form hydrogen bonds with the oxygens of the internal clay surfaces and that this results in an increase in the mean angle between the Ni–O vector and the water dipole in the Ni²⁺ hydration shell. The results demonstrate the validity of our approach of using orientationally averaged correlation functions obtained from isotopic substitution studies of powder samples to investigate inherently anisotropic hydration structures in layered clays.