The Ghadames Basin is considered as huge intracratonic structure, which preserved over 4000 m of Paleozoic sedimentary succession deposited over the Precambrian Basement. The present work consists of an integrated interpretation of the Paleozoic interval in the Ghadames basin of southern Tunisia using well logs and calibrated seismic data. Thus, the adopted sequence stratigraphic approach allowed the identification of a total of 3 s-order sequences, bounded by Taconic, Caledonian, and Hercynian unconformities recognized as major tectonic discontinuities in the study area. The determined second-order sequences have been further subdivided into fourteen third-order sequences with their associated systems tracts, which are limited by sequence boundaries (SB), and presenting transgressive surfaces (TS), and maximum flooding surfaces (mfs). Each sequence is characterized by a unique stacking pattern and distinctive facies, thus reflecting the lithology and the corresponding depositional environment. These sequences are composed of claystone and sandstone facies deposited in varying depositional environments, ranging from a shallow marine setting during the Ordovician period to a deep marine environment during the Early Silurian. A complex deltaic environment was evidenced during the Late Silurian involving to a fluvial environment during the Devonian period. The integration of well logs and seismic data proved to be an efficient approach in the delineation of sequence stratigraphy, revealing in detail the spatial distribution and sequence organizations within the study area. These later are controlled by the relative sea level variations, with eustasy is being the dominant factor. The obtained results are mainly correlatable with the sequence stratigraphy of North African basins at a regional scale and Snedden and Lee chart (2010) at a global scale.