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Buried water reservoirs are increasingly being built to replace open aboveground municipal water supply reservoirs in urban areas to enhance water quality and utilize their surface footprint for other purposes such as public parks or placement of solar arrays. Many of these lifeline structures are in seismically active regions and, as such, need to be designed to remain operational after severe earthquake shaking. However, evaluating their seismic response is challenging and involves accounting for the interaction of the structure with the stored fluid and the retained soil; in other words, accounting for fluid–structure–soil interaction (FSSI). This paper presents a combined experimental–numerical study on the seismic behavior of buried water reservoirs while considering FSSI. Two series of centrifuge model tests were performed at different reservoir orientations to investigate one-dimensional (1D) and two-dimensional (2D) motion effects under full, half-full, and empty reservoir conditions. Corresponding numerical models were developed whereby the structure and the soil were represented by continuum Lagrangian finite elements, while the fluid was modeled via Arbitrary Lagrangian Eulerian formulation. Soil–structure and fluid–structure interface parameters were calibrated using the experimental measurements. The simulations successfully captured the measured reservoir responses in terms of accelerations, bending moment increments, and water pressures. The study found that the common assumption of plane strain is not applicable for reservoirs because their behavior was found to be truly three-dimensional (3D) whereby stresses accumulated at the corners. Furthermore, the full reservoir resulted in the highest seismic demands in the reservoir walls and roof while the empty reservoir yielded the highest base slippage. The study demonstrates that the complex reservoir seismic response is best captured by carrying out a 3D FSSI numerical simulation.