Scattered nearly throughout the state, but more common in the eastern half (eastern U.S. west to Iowa and Arkansas; China). Dry or more commonly mesic upland forests on acidic substrates, on stream banks, slopes, and ridgetops; also occasionally on sandstone ledges.

For a discussion of further vegetative characters to distinguish L. liliifolia from the related L. loeselii, see the treatment of that species. There have been no studies to confirm the insect pollinators for large twayblade, although flies and other insects have been observed to visit the flowers. Some botanists continue to spell the specific epithet incorrectly, “lilifolia.”