Coastal NW South China Sea is a critical region for evaluating the contrasting thermo-tectonic histories between the onshore and offshore regions, and the possible surface response to a deep-seated mantle anomaly. To further elucidate the regional post-late Mesozoic tectonic cooling history, low temperature thermochronological data are reported from 16 onshore granite samples. These new data, together with previously reported data, are used to constrain the thermo-tectonic evolution of the onshore southern margin of the South China Block (SCB). Results show that the area has mostly experienced a similar three-stage cooling pattern, characterized by a ~3–8 °C/Myr Early Cretaceous to early Late Cretaceous (~130- ~80 Ma) cooling phase, followed by a period of relative thermal quiescence, and then a further cooling episode initiated in the early Eocene and for most samples continuing until the present day. The early cooling phase is recorded extensively along the southern SCB margin and is probably a combined response to several alternating compressional and extensional tectonic events during the Late Jurassic to early Late Cretaceous (~150- ~80 Ma). The second phase of relative thermal quiescence suggests, in contrast to the offshore and the eastern coast, that the onshore southern SCB margin was not affected markedly by compressional tectonics during the latest Cretaceous. Post-Eocene enhanced cooling and exhumation are probably related to widespread Eocene to Early Oligocene extension, and subsequent uplift due to convergence between the Indo-Australian, Eurasian and Pacific Plates in the onshore southern SCB margin. Southeastward extrusion due to Indo-Asia collision resulted in a decrease in uplift amplitude from NW to SE, but is not recorded in the offshore region. Different tectonic effects result in spatial relief variation from the onshore to the offshore southern SCB margin in the latest Cretaceous obviously different from in the late Cenozoic. NE Hainan Island, which was most likely mountainous during the Late Cretaceous to Paleocene, but became an area of low elevation and relief with gradual exhumation, particularly following significant Eocene–Early Oligocene exhumation. Neogene thermal histories in coastal NW South China Sea do not record any marked cooling rate changes which could be related to significant recent surface uplift and erosion, indicating that the deep anomalous body beneath the Leiqiong Depression might be just a branch of a much larger low-velocity anomalous structure. Our results suggest that the thermo-tectonic evolution of the onshore southern SCB margin (Guangdong) was mainly controlled by Cretaceous NE-trending subduction of the Palaeo-Pacific plate beneath the southeastern SCB, whilst during the Late Cenozoic it was mainly affected by the convergence of adjacent plates, particularly by the Indo-Asia collision.