Safe isolation of high-level radioactive waste (HLW) and spent nuclear fuel (SF) from the biosphere is an important concern for humanity. Many countries consider monitoring the evolving conditions of a HLW/SF repository over a long period noninvasively, in such a way as to not compromise the sealing of the repository. Remote active seismic methods are possible options. We performed extensive seismic measurements at the Mont Terri Rock Laboratory, located within a clay formation that is a potential host rock in the Swiss HLW/SF program. A scaled-down HLW/SF repository was simulated as a 13-m-long microtunnel of 1 m diameter. The dry sand-filled microtunnel was progressively water saturated and slightly overpressured. The monitoring system consisted of a pressure seismic source and a hydrophone cable located in two boreholes drilled perpendicular to the microtunnel and eight geophones equally distributed around the periphery of the microtunnel. Nonlinear anisotropic tomography of crosshole traveltimes allowed the gross velocity structure of the host rock to be determined, but due to the experiment geometry, the hydrophone traveltimes were inadequate for monitoring changes within the repository. In contrast, analysis of the geophone seismic traces enabled the saturation process to be characterized. An integrated interpretation of the geophone data in combination with extensive numerical modeling suggested that injection of the water resulted in significant self sealing of the microtunnel’s excavation damage/disturbed zone (EDZ) and substantial increases in the P-wave velocity of the microtunnel sand and EDZ. On the basis of our investigations, we concluded that seismic monitoring of a HLW/SF repository is feasible, as long as the sensors are installed as close to the repository as regulations allow.