An in-depth analysis of the petroleum geology and hydrocarbon accumulation within the Santos Basin has been conducted to assess its resource potential and to outline future exploration strategies. This study used established methods to characterize oil and gas reservoirs. Through the stratigraphic analysis and play-based assessment of the basin's hydrocarbon resources, two distinct geological combinations have been identified: the presalt and postsalt source-reservoir-seal combinations. The lacustrine mudstones of the Lower Cretaceous Picarras Formation, which are presalt in age, have been recognized for their substantial hydrocarbon generation potential. In the eastern part of the basin, the carbonate rocks from the Barra Velha and Itapema formations have been identified as the primary reservoirs. These rocks exhibit high-quality properties essential for hydrocarbon accumulation. The Ariri Formation's salt rocks, which act as the critical seals, are characterized by their considerable thickness, extensive areal distribution, and effective sealing properties. Two principal hydrocarbon accumulation models have been delineated for the Santos Basin: the presalt model, which is a “lower source-upper reservoir-salt seal” combination within carbonate strata, and the postsalt model, which is characterized by an “self source-self reservoir-self seal” within clastic sandstones. The large-scale hydrocarbon accumulation in the presalt strata is significantly influenced by the presence of high-quality source rocks, inherited ancient uplifts, and the continuity of massive salt formations. The late-stage injection and migration of CO2 have been identified as pivotal factors in shaping the types of presalt hydrocarbon reservoirs. Future oil and gas exploration in the Santos Basin is projected to prioritize the presalt domain. The focus will be on the eastern uplift belt and the central depression belt, with particular attention given to the high-in-sag regions within the central depression belt, which are considered strategic exploration targets. Conversely, postsalt exploration will likely concentrate on the western uplift belt where salt is either absent or thinly developed. In these regions, turbidite sandstone complexes are anticipated to be the main targets for hydrocarbon exploration.