The evolution of basinal brines through percolation into basement rocks is studied in the Paleo- to Mesoproterozoic Athabasca Basin and its underlying basement. This specific geological context includes the evolution of a NaCl-rich basinal brine to a U-mineralizing CaCl2-rich brine that is of particular importance for the understanding of the formation of giant U deposits. The objective of this study is to determine the physico-chemical parameters (P-T-X) of the basinal brines and their changes both within the Athabasca Group sandstones and the underlying basement lithologies, on the scale of several km around the world class unconformity-related Cigar Lake U deposit.Particularly, this study focuses on the basement-hosted fault systems that are considered to be the main fluid flow pathways. A comprehensive study including microthermometry, Raman spectroscopy, and LA-ICP-MS analyses was carried out on fluid inclusions, as was a semi-quantitative estimation of the microfracture paleoporosity based on the surface density of fluid inclusion planes.Initial NaCl-rich brines were trapped during early diagenesis (c.a. 1.7–1.65 Ga) in dickite-rich sandstones, under a three to seven kilometers thick sedimentary cover at around 90 to 150 °C under hydrostatic pressure, or at 120–210 °C assuming lithostatic conditions. At the time of U deposits formation (ca. 1.46–1.29 Ga), these brines percolated through the entire basement, but preferentially within the damage zones of some graphite-rich faults, formed during the ca. 1.8 Ga Trans-Hudson Orogeny and active during the subsequent retrograde metamorphism and exhumation (ca. 1.8–1.72 Ga). The circulation of the basinal brines into these structures was enhanced and structurally-controlled by the microfracture network inherited from earlier brittle reactivation during basement uplift. The resulting high microfracture paleoporosity in the vicinity of some, but not all, of these structures favored intense interaction between the brines and basement rocks that induced the formation of illite-sudoite alteration haloes. In the basement, the percolating brines scavenged Mn, K, Ba, Sr, and especially U, and evolved from the original NaCl-dominant composition toward a higher salinity CaCl2-rich composition. The resulting U-bearing brine mixed with the unmodified diagenetic NaCl-rich brine in, above, and all along the reactivated faults, either during thermal convection in isobaric settings and higher temperatures (110–200 °C) or through episodic tectonic reactivation in isothermal settings through episodic pressure fluctuation. In direct vicinity of the U deposits, the interactions between the brines and the basement rocks were the strongest, which is marked by the highest intensity of alteration of the host rocks.Thus, the formation of ore-forming fluids resulted from the interaction between NaCl-rich basinal brines and highly-microfractured basement rocks. This study reinforces the hypothesis that interaction with basement rocks enhanced by strong fluid flow in cataclastic zones, can significantly modify the physico-chemical characteristics of basin-derived brines, leading to the formation of mineralizing fluids and the genesis of giant ore deposits, such as the unconformity-related U deposits.