This work provides new petro-geochemical and isotopic information to constrain the crustal evolution of the Precambrian Cerro La Ventana Formation. The Rb–Sr, Sm–Nd, Pb–Pb, and U–Pb isotopic data obtained as well as their petrological and geochemical features are reported. These data are useful to discuss relationships with equivalent Mesoproterozoic units located along the Cuyania terrane in the proto-Andean Gondwana margin. The type section of the basement rocks of the Cerro La Ventana Formation is located in the south-eastern part of the San Rafael Block, Mendoza Province known as Leones-Ponón Trehué-La Estrechura region. Equivalent crustal fragments are also included in this basement, such as ductile-deformed rocks of the El Nihuil Mafic Unit that are intruded by Ordovician undeformed dolerites. The basement exposed along the type section corresponds to a metamorphosed volcano-plutonic complex with hardly any sedimentary protolith. Main rocks are tonalites and foliated gabbros and quartz diorites that pass to amphibolites, and minor granodioritic–dioritic orthogneisses, with abundant angular microgranitoid enclaves now deformed and stretched intruded in mafic to felsic metavolcanics with porphyritic relic textures. The studied samples classified as tonalites and some close to the field of granodiorites following a calc-alkaline trend. Gabbroic samples from the El Nihuil mafic unit show a more tholeiitic signature. The bulk of samples from the Cerro La Ventana Formation plot within the field of metaluminous rocks; although a few are in the peraluminous field. Main groups of samples plot as low-Al TTD field; however, some of them show high Sr/Y ratios which are typical of high-Al TTD. The Mg#/K ratio is higher in the Cerro La Ventana Formation compared with Las Matras TTG series suggesting a minor differentiated grade for the first one. The chondrite-normalized REE diagrams for Leones samples have Eu anomalies rather positive and gabbros from El Nihuil region display patterns with positive Eu anomalies typical of plagioclase-rich igneous rocks. The Rb–Sr data defined an isochron with 1148 ± 83 Ma, initial 87Sr/86Sr = 0.70292 ± 0.00018. The low initial ratio is indicative of a slight evolved Mesoproterozoic source. An acceptable isochron was obtained using Sm–Nd methodology indicating an age of 1228 ± 63 Ma. The model ages (TDM) are in the range 1.23–1.64 Ga with εNd(1200) in between −0.94 and +4.7 recording a ‘depleted’ source, less evolved than CHUR for the time of crystallization. In a 207Pb/204Pb diagram the samples plot similarly to rocks from the basement of Cuyania Terrane (Pie de Palo Range and crustal xenoliths) showing a distinctive non-radiogenic signature. The tonalitic lithofacies located at the Leones River type section was chosen for zircon U–Pb TIMS dating and the obtained crystallization age was 1214.7 ± 6.5 Ma. The in situ U–Pb (LA-ICP-MS) zircon data done in two different laboratories on samples from El Nihuil mafic unit (tonalitic orthogneisses) plotted in a Concordia diagram, record an intercept at 1256 ± 10 Ma and in Tera-Wasserburg diagram an age of 1222 ± 6.9 Ma. With these isotopic data we confirm the Mesoproterozoic age for the basement of the San Rafael Block. The obtained ca. 1.2 Ga is quite similar to those belonging to the basement of other regions from the Cuyania allochthonous terrane.