Abstract: The Pearl River Mouth Basin (PRMB) is rich in oil and gas resources in the Cenozoic, with proven reserves growing rapidly. Geological breakthroughs, such as the identification of hydrocarbon accumulation controlled by low-angle detachment faults, strike-slip fault-controlled reservoirs in buried hills through weathering and leaching processes, and multi-type reservoir enrichment in deep-water areas, have offered new insights into exploration targets in PRMB. However, the complex geological structure and diverse target types in the basin increase the difficulty of exploration. Therefore, under the guidance of breakthroughs in exploration theory, it is crucial to reassess the Cenozoic oil and gas geological conditions in PRMB and identify potential oil and gas exploration zones. Through comprehensive analysis of the tectonic-sedimentary coupling relationships, hydrocarbon source rock and reservoir conditions, and oil and gas migration characteristics in PRMB, the oil and gas-bearing probability in different zones of PRMB was evaluated, and the total geological resource amount of the Cenozoic was calculated. The PRMB experienced significant tectonic evolution during the Cenozoic, characterized by rifting, post-rift depression, and structural activation. This evolution resulted in the formation of continental, transitional, and shallow marine sedimentary filling features, which controlled the development of two Paleogene hydrocarbon source rocks and two sets of continental and marine reservoirs. The oil and gas geological conditions in the shallow-water areas of the Lufeng, Huizhou, and Wenchang sags were favorable, with oil and gas-bearing probability exceeding 20% and relatively low geological risks. Therefore, these areas were classified as Class Ⅰ favorable zones. The total geological resource amount of the Cenozoic was approximately 13.8 billion tons, with oil accounting for 71% and natural gas 29%. Based on zone evaluation and actual exploration cases, future exploration should focus on buried hills, Paleogene, and deep-water oil and gas reservoirs, especially searching for those in low-angle detachment faults of the Enping, Kaiping, and Baiyun sags, fractured reservoirs controlled by deep strike-slip faults in buried hills of the Wenchang and Yangjiang sags, and deep-water reservoirs in the Baiyun and Liwan sags. These sags are expected to become important potential exploration zones for future oil and gas exploration in PRMB.