Highly fractionated granites and related magmatic-hydrothermal ore-forming processes can be traced by elemental ratios such as Nb/Ta, K/Rb, Y/Ho, Sr/Eu, Eu/Eu*, Zr/Hf, and Rb/Sr. The lanthanide “tetrad effect” parameter (TE1,3) can also be a useful geochemical fingerprint of highly fractionated granites. This work assesses its application as an exploration vector for granite-related mineralization in the Central Iberian Zone by examining TE1,3 variations with different elemental ratios and with the concentrations of rare metals and fluxing elements (such as F, P, and B). The multi-elemental whole-rock characterization of the main Cambrian–Ordovician and Carboniferous–Permian granite plutons and late aplite–pegmatite dykes exposed across the Segura–Panasqueira Sn-W-Li belt show that the increase in TE1,3 values co-vary with magmatic differentiation and metal-enrichment, being the Carboniferous–Permian granite rocks the most differentiated, and metal specialized. The Argemela Li-Sn-bearing rare metal granite and the Segura Li-phosphate-bearing aplite–pegmatite dykes deviate from this geochemical trend, displaying TE1,3 < 1.1, but high P2O5 contents. The results suggest that mineralized rocks related to peraluminous-high-phosphorus Li-Sn granite systems are typified by TE1,3 < 1.1, whereas those associated with peraluminous-high-phosphorus Sn-W-Li (lepidolite) and peraluminous-low-phosphorus Sn-Ta-Nb granite systems display TE1,3 > 1.1, reaching values as high as 1.4 and 2.1, respectively.