In Asia, the record of their history suggests they grew gradually larger and more predatory over time, then shifted to scavenging and bone-crushing lifestyles before the group became extinct.

Dissacus was a jackal-sized predator that has been found all over the Northern Hemisphere,[3] but species of a closely related or identical genus, Ankalagon, from the early to middle Paleocene of New Mexico, were far larger, growing to the size of a bear.

While later mesonychians evolved a suite of limb adaptations for running similar to those in both wolves and deer, their legs remained comparatively thick.

They may not have included hypercarnivores (comparable to felids); their teeth were not as effective at cutting meat as later groups of large mammalian predators.

[5] These "wolves on hooves" were probably one of the more important predator groups in the late Paleocene and Eocene ecosystems of Europe (which was an archipelago at the time), Asia (which was an island continent), and North America.

A recent study found mesonychians to be basal euungulates most closely related to the "arctocyonids" Mimotricentes, Deuterogonodon and Chriacus.

For this reason, scientists had long believed that mesonychians were the direct ancestor of Cetacea, but the discovery of well-preserved hind limbs of archaic cetaceans, as well as more recent phylogenetic analyses[8][9][10] now indicate cetaceans are more closely related to hippopotamids and other artiodactyls than they are to mesonychians, and this result is consistent with many molecular studies.

[11] The similarity in dentition and skull may be the result of primitive ungulate structures in related groups independently evolving to meet similar needs as predators; some researchers have suggested that the absence of a first toe and a reduced metatarsal are basal features (synapomorphies) indicating that mesonychians, perissodactyls, and artiodactyls are sister groups.

The current uncertainty may, in part, reflect the fragmentary nature of the remains of some crucial fossil taxa, such as Andrewsarchus.