Compared to the larger (but not closely related) Hyainailouros, the dentition of Hyaenodon was geared more towards shearing meat and less towards bone crushing.

H. microdon and H. mustelinus from the late Eocene of North America were even smaller and weighed probably about 5 kg (11 lb).

Juveniles took about 3–4 years to complete the final stage of eruption, implying a long adolescent phase.

[23] The various species of Hyaenodon competed with each other and with other hyaenodont genera (including Sinopa, Dissopsalis and Hyainailurus), and played important roles as predators in ecological communities as late as the Miocene in Asia and preyed on a variety of prey species such as primitive horses like Mesohippus, Brontotheres, early camels, oreodonts and even primitive rhinos.

[20] Species of Hyaenodon have been shown to have successfully preyed on other large carnivores of their time, including a nimravid ("false sabertooth cat"), according to analysis of tooth puncture marks on a fossil Dinictis skull found in North Dakota.