New thermobarometric and U/Pb and 40Ar/39Ar geochronologic data coupled with ages obtained from the Acatlán Complex, the basement of the Mixteco terrane of southern Mexico, reveal the existence of three distinctive high-pressure metamorphic events of early to middle Paleozoic age, each recorded in a separate lithological suite. Xayacatlán suite eclogites with oceanic affinity underwent peak metamorphism at 609–491 °C and 13–12 kb during the Early Ordovician (ca. 490–477 Ma, U-Pb zircon), followed by a partial overprint at 600 °C and ∼9.6 kb and then at 500 °C and ∼6.7 kb. An overprinting event at 525–500 °C and ∼9.5 kb is ascribed to the Devonian. The pressure-temperature (P-T) path of the Xayacatlán suite indicates a subduction-exhumation process followed by tectonically related reburial. Ixcamilpa suite blueschists with oceanic affinity underwent epidote-blueschist metamorphism (T, 200–390 °C; P, 6–9 kb) and then epidote-amphibolite (T, 390–580 °C; P, 9–6 kb) events ascribed to the Late Ordovician–Early Silurian. Esperanza suite eclogites with continental affinity underwent peak metamorphism at 830–730 °C and 17–15 kb. Amphibole from eclogite yields a 430 ± 5 Ma 40Ar/39Ar age, dating the high-pressure (HP) event. P-T paths of high-temperature (HT) eclogites like those of the Esperanza suite have been related to the collision of continental blocks. Partial overprinting occurred at 690–640 °C and 14–10 kb prior to 374 ± 2 Ma (40Ar/39Ar, phengite). The three HP suites were tectonically juxtaposed at different times before the Mississippian Period, resulting in the closure of the Iapetus Ocean. Phengite 40Ar/39Ar geochronology reveals the existence of a widespread tectonothermal event between 345 and 323 Ma, which may be related to the juxtaposition of the HP-composed block and the Gondwanan-affinity Cosoltepec suite, causing the closure of the Rheic Ocean. The tectonothermal events in the Acatlán Complex coincide in time, physical conditions, and tectonic setting with events in the Appalachian-Caledonian orogen, suggesting their relation. On that basis the geology of the Acatlán Complex can lead to a more comprehensive understanding of the tectonic evolution of the Appalachian orogen and of the Gondwana-Laurentia interactions preceding the Pangean assembly.