We describe one of the oldest notoungulate skeletons with associated craniodental and postcranial elements: Thomashuxleya externa (Isotemnidae) from Cañadón Vaca in Patagonia, Argentina (Vacan subage of the Casamayoran SALMA, middle Eocene). We provide body mass estimates given by different elements of the skeleton, describe the bone histology, and study its phylogenetic position. We note differences in the scapulae, humerii, ulnae, and radii of the new specimen in comparison with other specimens previously referred to this taxon. We estimate a body mass of 84 ± 24.2 kg, showing that notoungulates had acquired a large body mass by the middle Eocene. Bone histology shows that the new specimen was skeletally mature. The new material supports the placement of Thomashuxleya as an early, divergent member of Toxodontia. Among placentals, our phylogenetic analysis of a combined DNA, collagen, and morphology matrix favor only a limited number of possible phylogenetic relationships, but cannot yet arbitrate between potential affinities with Afrotheria or Laurasiatheria. With no constraint, maximum parsimony supports Thomashuxleya and Carodnia with Afrotheria. With Notoungulata and Litopterna constrained as monophyletic (including Macrauchenia and Toxodon known for collagens), these clades are reconstructed on the stem to Euungulata (i.e., Perissodactyla and Artiodactyla). Unconstrained, Bayesian analysis weakly supports the possibility that Thomashuxleya is a stem xenarthran; with Notoungulata and Litopterna constrained as monophyletic, the two clades are recovered as sister to Perissodactyla. Anatomical data sampled thus far for Thomashuxleya, combined with collagen amino acids for Pleistocene meridiungulates, substantially limit the number of possible affinities for endemic South American species among mammals, although ambiguity still remains.