A high degree of uncertainty exists for understanding and predicting coastal estuarine response to changing climate, land-use, and sea-level conditions, leaving geologic records as a best-proxy for constraining potential outcomes. With the majority of the world's population focused in coastal regions, understanding how local systems respond to global, regional, and even local pressures is key in developing mitigation, adaptation, and management plans. The geomorphology of Mobile Bay in southeast Alabama (USA) has evolved considerably (e.g., bayhead delta back-stepping) over the late Holocene in response to global and regional sea-level and climate change. Smaller-scale geomorphic changes (e.g., spit and beach ridge development) have also had a significant influence on the evolution of the estuary. Organic matter characteristics, inorganic sediment geochemistry, benthic microfossils, and pollen in a ~ 3500 cal yr BP sediment sequence recovered in a gravity core (20GC) from Bon Secour Bay, a small sub-bay in the southeast corner of Mobile Bay, record time-varying marine influence. Increases in marine influence during ~3500 to 2300 cal yr BP and 1930 to 1160 cal yr BP are defined as zones with high-density and pre-dominantly calcareous foraminiferal species, abundant sand (>10%) and more marine-like geochemical signatures, which contrast the low-density and pre-dominantly agglutinated foraminiferal and more terrestrially influenced estuarine muds observed in other intervals of the sedimentary record (2300–1930 and 1160–400 cal yr BP) and the modern bay. Hydrodynamic models constrained by geomorphic boundary conditions for the time ~ 3500 cal yr BP, consistent with the most prominent marine-influenced sediment, provide insight to potential coastal configuration that might have permitted such marine water intrusion into the bay. Of several scenarios evaluated, a breach in Morgan Peninsula produces tidal circulation within the basin supportive of persistent marine incursions in the bay between ~3500 to 2300 cal yr BP. The findings show that slight variations in coastal configuration can have broad-scale effects on bays and estuaries with consequences that may relate to water quality, vertebrate and invertebrate habitat, and coastal vulnerability to episodic events like (extra)tropical storms.