The Paleozoic era begins with the final assembly of Gondwana and ends with the amalgamation of the supercontinent Pangea. Although this tectonic progression is generally well documented, one fundamental but under-studied phenomenon during this era is the transition from two-way to one-way (northward) migration of peripheral terranes between Gondwana and Laurentia-Baltica from Cambrian to Ordovician time. The two-way terrane accretion was likely initiated during the opening of the Rheic Ocean at ca. 510 Ma when several Gondwana-derived terranes comprising Carolinia, Ganderia, Avalonia, and Meguma sequentially drifted from the northern margin of Gondwana and eventually collided with Laurentia or Baltica. Over the same time interval, the Laurentia-derived Cuyania terrane (a.k.a., the “Precordillera terrane” is commonly believed to have accreted to the proto-Andean margin of Gondwana, whereas the peri-Laurentian/Dashwoods ribbon continent separated from, then re-accreted to, the Laurentian margin after being trapped during the collision of the Taconic arc. Alternatively, the Cuyania terrane is suggested to have remained attached to the Ouachita Embayment throughout the Cambrian–Ordovician, and then passed onto Gondwana during the collision between the proto-Andean margin and the hypothesized Texas Plateau at the leading edge of Cuyania. Here we explain the enigmatic, pene-contemporaneous migration of these peripheral terranes by a trans-Iapetus transform fault that was likely active between 510 and 450 Ma and extended from the proto-Appalachian margin of Laurentia to the proto-Andean margin of Gondwana. The trans-Iapetus transform fault terminated after the respective accretion of Carolinia and Ganderia to the proto-Appalachian margin and of Cuyania to the proto-Andean margin. We interpret the development of the trans-Iapetus transform during the Cambrian–Ordovician to be a consequence of the global geodynamic transition from the break-up of Rodinia (continents/terranes drifting away from Laurentia) to Pangea amalgamation (continents/terranes drifting toward assembling Laurussia).