Commonly known as the Carolina sphinx moth and the tobacco hawk moth (as adults) and the tobacco hornworm and the Goliath worm (as larvae), it is closely related to and often confused with the very similar tomato hornworm (Manduca quinquemaculata); the larvae of both feed on the foliage of various plants of the family Solanaceae.

M. sexta has mechanisms for selectively sequestering and secreting the neurotoxin nicotine present in tobacco.

[citation needed] M. sexta is a common model organism, especially in neurobiology, due to its easily accessible nervous system and short life cycle.

The final instar consists of a cylindrical body covered with fine hairlike setae.

When the larva feeds on its normal diet of plant foliage, it ingests pigmentacious carotenoids, which are primarily yellow in hue.

Under laboratory conditions—when fed a wheat-germ-based diet—larvae are turquoise in color due to the lack of carotenoids in their diet.

The M. quinquemaculatacaterpillar has V-shaped white markings with no borders at all eight of its abdominal segments, and the horn is dark blue or black in color.

[6] During the larval stage, M. sexta caterpillars feed on plants of the family Solanaceae, principally tobacco, tomatoes and members of the genus Datura.

The imminence of pupation—suggested behaviorally by the wandering—can be anatomically confirmed by spotting the heart (aorta), which is a long, pulsating vessel running along the length of the caterpillar's dorsal side.

Parasitized hornworms are often seen covered with multiple white, cottony wasp cocoons, which are often mistaken for large eggs.

M. sexta moths are nectarivorous and feed on flowers, demonstrating a remarkable ability to hover.

Mating generally occurs on a vertical surface at night, and can last several hours, with the male and female facing in opposite positions, their posterior ends touching.

They are frequently studied in the laboratory due to their large size and relative ease of rearing.

Their rearing is straightforward, provided they receive a long daylight cycle (e.g., 14 hours) during development to prevent diapause.

Providing a cup of sugar water and a tobacco (or related) plant will allow mated females to oviposit fertile eggs, which can then be reared.

When fed an artificial diet, Manduca larvae do not consume the xanthophyll -which is a yellow pigment- needed to produce their green coloration; instead they appear blue.

[8] Captive-bred hornworms fed on an artificial diet are often given to insectivorous exotic animals, such as certain reptiles, fish and small mammals.

[16] Schoonhoven 1969 found that M. sexta habituation to salicin is mediated by desensitization of the deterrence associated peripheral neurons and Glendinning et al. 1999 the same for caffeine.

[16] However Glendinning et al. 2001 find only a small peripheral desensitization for salicin, concluding that Schoonhoven erred, and that habituation in this case is centrally mediated.

When dehydrated, tobacco hornworm larvae will move towards a source of water or to an area with a high relative level of humidity.