Archaeological evidence indicates that Native American groups from the Marksville culture were present near the shores of Sabine Lake by 500 CE.

Burial mounds that may have belonged to the Karankawa have been uncovered near the north shore at what is now Port Neches, but by the time of European arrival in the eighteenth century the region was inhabited by the Atakapa.

The lake's shores were only intermittently settled and abandoned in the mid-to-late 1800s, and the 1886 Indianola hurricane destroyed the only significant settlements nearby at Sabine Pass and Johnson Bayou.

[3] The discovery of petroleum under Spindletop in 1901 began the Texas oil boom and caused rapid economic growth in nearby Beaumont, prompting interest in expanding the region's canal system.

The lake's small size and high rate of freshwater inflow make it the least saline of the major Texas estuaries.

[8]: VI–13  Aquatic fauna include a variety of finfish and shellfish, with large populations of sport fishing species such as Atlantic croaker, spotted seatrout, southern flounder, red and black drum, sheepshead and gafftopsail catfish.

[8]: VI–12  These coastal wetlands provide habitats for American alligators, Atlantic ridley sea turtles, red wolves and brown pelicans.

[8]: III–14  Saltwater intrusion and land subsidence resulting from human activities in the lake since the late 1800s have caused vegetation loss and erosion, and the remaining marshes are experiencing ongoing degradation as the ecosystems adjust to the altered hydrology in the estuary.

Agriculture also forms a significant component of the regional economy, principally rice and soybean cultivation, livestock ranching, and commercial fishing.