Prognathodon has been recovered from deposits ranging in age from the Campanian to the Maastrichtian in the Middle East, Europe, New Zealand, Africa and North America.

Due to the sometimes clear differences between them and the incomplete nature of many of the specimens, the systematics of the genus and which species should properly be considered Prognathodon is controversial.

Large amounts of work was commonly invested in extracting and mounting the specimens, but scientific study of them remained limited with diagnoses and descriptions mainly focusing on peculiar points of their anatomy, such as the quadrate and tympanic membrane of Plioplatecarpus houzeaui.

[6] Two specimens of Prognathodon overtoni described in 2011 from the early late Campanian (c. 74.5 Ma) Bearpaw Formation in Alberta, Canada provided the first fully articulated skeletons of the genus.

Detailed studies of these and previously discovered specimens allowed several characters to be established that distinguishes Prognathodon from closely related genera like Liodon and long-snouted mosasaurines.

Carlo Brauer, an excavator operator at the ENCI quarry, discovered the teeth of the fossil in the shovel of his digger on Monday morning, September 10.

In the days following the discovery, museum staff retrieved several large sections of the skull and part of the body and tail of the approximately 13-metre long skeleton.

The function of the scleral ossicles is to maintain the shape of the cornea and support the sclera in the region of Brucke's muscle responsible for affecting accommodation in the lacertilian eye.

[3] The latest published diagnosis for the genus Prognathodon was provided by Lingham-Soliar and Nolf (1989),[2] and states that the premaxilla lacks a rostrum anterior to the premaxillary teeth.

[19] The quadrates of Prognathodon, similarly to the genus Globidens, have fused suprastapedial and infrastapedial processes, which is possibly an adaptation to counteract the strong forces experienced by the bone during biting.

The coronoid is saddle-shaped and has a well-developed posterodorsal process, which gives the dorsal margin of said bone a nearly 110 degree angle between the horizontal anterior end and the subvertical posterior wing.

In addition to deep striae, the fragmentary material of P. solvayi reveals that the tooth crowns may also have been somewhat prismatic with seven to eight prisms on the external surface.

The teeth have a slight posterior and medial recurvature and are noted for having smooth surfaces (which is different from other species of Prognathodon) except for minor wrinkles at the tips of the tooth crowns.

The fossil is not only largely complete and articulated, which is rare for Prognathodon specimens, but also preserves significant portions of the integument and a gentle bend on the last few caudal vertebrae.

This helped in providing evidence that mosasaurs were convergent with ichthyosaurs, metriorhynchid thalattosuchians and whales in the evolution of a crescent-shaped tail fluke to aid in locomotion.

The lower fin lobe follows the caudal vertebrae and would have had a streamlined cross-section in life, based on the proportions of the axial skeleton and the other soft tissues.

[21] The proportions of the soft tissue structures and their relation to the skeletal elements of the specimen can be used to infer the shape and size of the fins in other species of Prognathodon and potentially in other mosasaur genera as well.

Louis Dollo was one of the earliest researchers to work on mosasaur systematics, initially placing them as a distinct lizard suborder and dividing the group into two families, the Mosasauridae and the "Plioplatecarpidae".

These groups were based on how developed the rostrum was on the premaxilla, the size of the suprastapedial process of the quadrate and if the haemal arches were fused to the centra of the caudal vertebrae.

[4] Gorden L. Bell Jr. conducted the first major phylogenetic analysis of mosasaurs in 1997, utilizing new methodologies and incorporating further taxa described since Russell's 1967 monograph (particularly basal mosasauroids, such as Aigialosaurus).

Cau and Madzia (2017) noted that the inclusion of Prognathodon and Plesiotylosaurus within the Globidensini would suggest a closer relationship between the genera than the reality of the situation.

Though Prognathodon and Plesiotylosaurus are routinely recovered as sister genera, Cau and Madzia (2017) did not resurrect the tribe Prognathodontini in their list of mosasaur clades and their preferred definitions, offering no comment as to why not.

Lindgren (2005)[25] pointed out that robust and conical tooth crowns with blunt, serrated carinae and smooth enamel are routinely assigned to the genus, despite the generic type species, P. solvayi deviating from that description since it exhibits markedly labio-lingually compressed and gently facetted marginal teeth.

Notably, the exclusion of the six controversial species significantly shortens both the temporal and geographical range of the genus, limiting it to Europe and the Middle East and removing any occurrence before the Late Campanian.

The presence of serrated carinae would suggest that Prognathodon instead was an opportunistic predator comparable to modern killer whales, rather than particularly adapted to crush its prey.

[2] Prognathodon overtoni, likely similar in ecology to other species of the genus, was thus likely an opportunistic predator capable of feeding upon nearly anything in the Western Interior Seaway.

The likely cause of death of the specimen was age or disease, due to marine predators large enough to kill something of its size being unknown from the Maastrichtian.

The degree of articulation of the specimen suggests that the animal reached the sea floor moments after its death, where it was scavenged by sharks prior to being buried by the sediments.

[5] A Prognathodon specimen known as NHMM 2012 (often nicknamed as "Carlo"), described by Bastiaans et al. in the journal Cretaceous Research in 2020, was discovered in the Netherlands near Maastricht, and was shown to have severe facial deformities including a devastating partial amputation of the premaxilla.

Unlike modern reptilians where solid fibrous masses are produced to contain infections, this mosasaur showed a much more mammal-like response, including liquid pus.