Uranium, hydrogen, and oxygen isotopes in groundwater reveal different nature of water-rock interaction processes in structures of the Baikal Rift System (BRS) inherited the Main Sayan Fault (MSF) zone and developed in the adjacent Archean Sharyzhalgay block of the Siberian paleocontinent basement. For fresh cold groundwater of the upper hydrogeodynamic floor, in the Kultuk reservoir of the MSF zone, a two-component mixing model is substantiated, initially obtained from U and Sr isotopes and confirmed by H and O ones in this work. The δ²Н and δ¹⁸О values increase with increasing content of dissolved silicon. The trend of the lower hydrogeodynamic floor is exhibited by thermal waters of the Baunt basin, in which the δ²Н and δ¹⁸О values decrease with increasing content of dissolved silicon. In the U-H-O isotope systematics at the stations of hydrogeochemical monitoring of seismic hazard in the BRS, the special significance of the geochemical signatures of groundwater obtained for the spring at station 143A of the Kultuk area is emphasized. A higher activity ratio of ²³⁴U/²³⁸U (AR4/8) was determined for waters from this station as compared with groundwater from the MSF of the Kultuk reservoir. The geochemical signatures of water from station 143A partially correspond to those from the Kultuk reservoir in the MSF zone, and partially to geochemical signatures of the groundwater from the northwestern coast of Lake Baikal and the eastern coast of the Irkutsk reservoir. It is proposed that the groundwater of these areas includes a component of the deep water from the South Baikal reservoir (SBR). The difference in the U-H-O isotope signatures of water from the spring of station 143A and the Kultuk reservoir in the MSF is explained by the structural control of this spring by an arc fault of the Circum-Baikal Railway, arranged in the Archean Sharyzhalgai block of the Siberian paleocontinent margin, along the Obruchev fault. The revealed temporal decreasing in the OA4/8 values in water of the spring indicates present-day increasing in compression in the deep part of the arc fault. Continuation of this process can have catastrophic consequences – a large landslide into the South Baikal basin along the plane of the arc fault.