The effect of paleoclimate during global warming periods on Upper Cretaceous lacustrine deposits is not fully understood. In this study, comprehensive sedimentological, mineralogical, and geochemical data were used to unravel the past climatic changes and their influence on the accumulation of Campanian lacustrine organic-rich deposits in Egypt. Three sedimentary lithofacies associations are recorded within the uppermost part of the Quseir Formation. The laminated clay-rich mudstone lithofacies has the highest organic matter (TOC up to 1.2 wt.%). Sedimentological observations indicate that the bulk lithologic assemblage was originated in a shallow lacustrine setting. The studied samples consist of clay minerals, quartz, pyrite, carbonate, fluorapatite, and halite. The siliciclastic content reaches up to 78wt.%, whilst the carbonate content ranges from 3 to 22 wt.%. Compared to Post-Archean Australian shales (PAAS), the studied samples are significantly rich in Mg, Ca, P, Al, V, Ga, and Cr contents. The mudstone samples are characterized by high ratios (C-value, CIA, CIW, Mg/Ca, Fe/Mn, Ga/Rb) and low values (K2O/Al2O3), reflecting relatively warm and humid conditions during deposition of these sediments. The prevalence of smectite, as well as the sedimentary features, support that the lacustrine organic-rich mudstones are mainly deposited under warm seasonal climate (arid/humid). Additionally, the presence of dolomite and halite along with the Sr/Ba ratios (1.30–2.13), strongly suggest a saline water setting. The changes between aridity and humidity periods are probably the main reason for the significant variation in water chemistry, especially salinity. Therefore, the paleoclimatic variations largely controlled the depositional process during the formation of the Upper Cretaceous lacustrine organic-rich mudstones in the southern Tethys.