Sierd Cloetingh's work has involved thermo-mechanical modelling of lithospheric evolution constrained by analysis of geological data; it has provided deep insights into continental rifting, sedimentary basin evolution, and continental margin evolution. His research has compared features worldwide to identify fundamental processes. His early work used intraplate stress models in realistic geometries to explore phenomena including initiation of the Cocos-Nazca spreading centre by changes in the subduction of the Farallon plate, which demonstrated conditions under which a new spreading ridge could form. His studies of the Indian Ocean predicted intraplate stress levels that agreed with data from earthquakes, faulting, folding, heat flow, gravity, and plate motions; these predictions were confirmed when it was shown that deformation had progressed to the point that India and Australia are now best described as distinct plates. His work on continental margin stress fields was among the first to address the effects of both regional tectonic stresses and the depth-dependent strength of the lithosphere. These studies introduced the concept that some of the variations in relative sea level recorded in sedimentary sections are caused by variations in regional stress fields; this concept is supported by observations from several continental margins and sedimentary basins, and has important consequences for foreland basins and hence orogenic processes. His work on cratonic basin evolution has led the development of models that integrate diverse geological and geophysical observations and contribute to understanding the relationship between the tectonics and stratigraphy of cratons.
He has also played a role in advancing European geoscience through his work with the EGU and the Academia Europaea, through successful initiatives such as the TopoEurope programme, and by fostering the growth of Eastern European geosciences that helped bring researchers from these nations to the forefront of tectonic research.