Abstract: The Eastern Sub-sag of Huanghekou Sag is a typical marginal sag in the south of Bohai Bay Basin. Because the basin is shallow and small, the source rock distribution range is limited and the maturity is low, it does not have large-scale gas generation conditions, but a large amount of natural gas is developed far away from the source rock area. Based on more than 20 drilling data and three-dimensional seismic data and combined natural gas composition and isotope data, the distribution pattern and genesis of natural gas in the study area was analyzed, the lateral migration mechanism of natural gas was clarified, the main controlling factors of oil and gas differential distribution were untangled, and the oil and gas differential reservoir formation model established. Results indicate that the natural gas is of secondary transformation origin, derived mainly from degraded crude oil from the primary oil reservoir. Under the joint control of regional cap rocks with differential sealing abilities, widespread sand bodies, and fluid potential energy of oil and gas, the natural gas migrates and accumulates steadily towards high structural areas below the bottom cap of the Pliocene Upper Member of Minghuazhen Formation to form reservoirs. The Eastern Sub-sag is characterized by differential hydrocarbon supply in small depressions, combined control of ridges and faults, and regional cap rock preservation for oil and gas accumulation. The natural gas reservoirs, as products of primary oil reservoirs, could guide the exploration of heavy oil reservoirs in low structural areas based on the estimation of natural gas scale. This study provided guidance for the exploration in basin-edge depressions with similar geological backgrounds.