Great blue lobelia grows in swamp forests, roadside ditches, floodplains, lake margins and wet prairies from Maine to Manitoba and south to North Carolina and Texas. VASCAN records it in Quebec and Ontario. Bumblebees are the main pollinators: a bee of the right weight presses down the lower petals to reach the nectar, which lowers the stigma against its back. The plant is short-lived, lasting only a few years.
The epithet siphilitica comes from a mistaken belief, held by early European settlers, that the plant cured syphilis. The genus honours the Flemish botanist Matthias de l'Obel. Native Americans have used the plant traditionally, according to published sources.