The ~183 Ma Karoo Continental Flood Basalt (CFB), southern Africa, formed during a period of major crustal extension prior to Gondwana breakup. To explain the ‘lithospheric contamination’ observed in its whole‐rock chemical and isotopic data various models have been proposed, such as different subcontinental lithospheric mantle (SCLM) sources or interaction between a mantle plume and SCLM or subducted material. A re‐assessment of data in the literature from the Northern Karoo Province, combined with new petrographic, whole‐rock chemical and Sr‐Nd isotopic data of basaltic and dacite/trachydacite samples from the southern Lebombo suggest that chemical diffusion between low‐Ti basaltic/picritic magmas and high‐SiO2 rhyolite parent melt may have caused this ‘lithospheric contamination’. Such slow chemical diffusion, which is posited to have developed during formation of this CFB, can explain the bimodal Karoo basalt‐rhyolite association, the wide variation in SiO2 content (~62–78 wt%) in the dacite/rhyolites, and variable 87Sr/86Sr (183 Ma) and ɛNd (183 Ma) isotope ratios of the Karoo picrites and basalts (0.7037 to 0.7102; 3.58 to −33.52, respectively) and dacites/rhyolites (0.7032 to 0.7152; 0.44 to −17.19). The intermediate incompatible trace element and isotopic compositions of the Karoo high‐Ti basalt/picrite suggest that these rocks could have evolved by magma mixing through chemical diffusion. Our geochemical model for the northern Karoo CFB province involves existence of a voluminous hot (>1,000°C) low‐Ti basaltic magma chamber with remnant picritic melts at shallow crustal depth (~4 km) during major crustal extension. Magma storage was relatively protracted, resulting in significant volumes of partial melt of the surrounding granitoids of the Kaapvaal Craton under relatively anhydrous condition, leading to generation of A‐type high‐SiO2 rhyolite parent magma at pressure of ~1.5 kbar and temperature of ~930°C. This was followed by chemical diffusion of selected elements [LREE, HFSE, and some LILE (K, Rb, Ba, Pb)] and self‐diffusion of Sr and Nd isotopes in these two melts, which generated the observed litho‐type variations in Karoo CFB.