Two new species of therocephalian therapsids are described from the upper Permian Teekloof Formation of the Karoo Basin, South Africa. They include two specimens of a whaitsiid, Microwhaitsia mendrezi gen. et sp. nov., and a single, small whaitsioid Ophidostoma tatarinovi gen. et sp. nov., which preserves a combination of primitive and apomorphic features. A phylogenetic analysis of 56 therapsid taxa and 136 craniodental and postcranial characters places the new taxa within the monophyletic sister group of baurioids—Whaitsioidea—with Microwhaitsia as a basal whaitsiid and Ophidostoma as an aberrant whaitsioid just outside the hofmeyriid+whaitsiid subclade. The new records support that whaitsioids were diverse during the early-late Permian (Wuchiapingian) and that the dichotomy between whaitsiid-line and baurioid-line eutherocephalians was established early on. The oldest Gondwanan whaitsiid Microwhaitsia and additional records from the lower strata of the Teekloof Formation suggest that whaitsioids had diversified by the early Wuchiapingian and no later than Pristerognathus Assemblage Zone times. Prior extinction estimates based on species counts are reflected in an analysis of origination/extinction rates, which imply increasing faunal turnover from Guadalupian to Lopingian (late Permian) times. The new records support a growing body of evidence that some key Lopingian synapsid clades originated near or prior to the Guadalupian-Lopingian boundary ca. 260–259 million years ago, but only radiated following the end-Guadalupian extinction of dinocephalians and basal therocephalian predators (long-fuse model). Ongoing collecting in older portions of the Teekloof Formation (e.g., Pristerognathus Assemblage Zone) will shed further light on early eutherocephalians during this murky but critical time in their evolutionary diversification.