Hydrocarbon exploration in the Berkine–Ghadames Basin in southern Tunisia has generally followed global economic trends. In recent years, improvements in seismic data acquisition combined with experience gained in log interpretation in low-resistivity reservoirs have resulted in oil and gas discoveries in the Upper Silurian Acacus Formation, enriching the hydrocarbon potential of the Berkine–Ghadames Basin in southern Tunisia. Presently, the Tunisian daily oil production is approximately 43,000 bbl, about half of which comes from the fields located in southern Tunisia and is produced from the Acacus Formation. The Berkine–Ghadames Basin is an intracratonic basin formed during the Pan-African Orogeny. It covers an area of approximately 350,000 km² (135,135 mi²) and extends into Algeria, Libya, and Tunisia. The sedimentary section within the basin ranges from Cambrian to present and is approximately 7000 m (23,000 ft) thick in the depocenter. The basin has experienced several tectonic events, which have modified its architecture and affected the petroleum systems and hydrocarbon pathways. In this study, the main elements of the petroleum geology systems are described. With the geochemical modeling results, the petroleum potential, hydrocarbon generation, expulsion time, and quantity of hydrocarbon are assessed. The main petroleum systems are also defined. They are represented by the Silurian Tannezuft hot shale source rock with Ordovician Djeffara and Silurian Acacus reservoirs, by Silurian Tannezuft hot shale with Kirchaou reservoirs, and by the Devonian Aouinette Ouinine Formation Member III source rock with Kirchaou reservoirs. The hydrocarbon traps in the area are mainly structural types. The study describes and emphasizes the hydrocarbon migration pathway mechanism from source rocks to traps. To predict and derisk future drilling locations, fairway maps are generated for the three plays: Ordovician, Silurian, and Triassic. Although the paper focuses on southern Tunisia, an attempt is made to introduce Libyan and Algerian knowledge to evaluate the basin in a regional context.