The Guyana Basin is located along the passive margin of northeastern South America. With no major oil discoveries, the region is considered by the U.S. Geological Survey the second least explored basin in the world. We integrated approximately 3000 km (similar to 1870 mi) of industry two-dimensional seismic data and 16 offshore wells in offshore Guyana to provide a regional framework and its hydrocarbon potential. Four main stratigraphic sequences from the Cretaceous to the Pliocene were recognized. Sequence 1 of the Cretaceous consists of shelfal sedimentation and submarine fan systems. The main Cretaceous depocenter is located in the southeastern part of the area, which coincides with a free-air gravity low, suggesting a basement depression inherited from Jurassic rifting. Sequence 2 of the Paleogene consists of shelfal clastic and carbonate deposits. Listric faults affect the shelf edge and slope, resulting in large turbidites down the slope. The west-southwest east-northeast oriented Waini arch developed along the northern shelf, and it may reflect a flexural long-distance effect of the Caribbean plate convergence with the northwestern South American plate. Sequence 3 of the early to middle Miocene consists of isolated carbonate platforms at the shelf edge surrounded by siliciclastics. On the sequence top, a regional unconformity was identified by large incised valleys. We suggest that this unconformity was caused by the peak of the Caribbean orogeny in the Trinidad area. Sequence 4 of the late Miocene to Pliocene shows the largest terrigenous progradational event in the shelf, which was built up by clear sigmoidal clinoforms. We suggest that the large progradation pattern change is caused by paleodrainage system changes in northern South America since the middle Miocene and by glacioeustasy.