[1] The family Hyainailouridae comprised a diverse group of hyaenodont predators that were most successful during the Eocene before being possibly ecologically displaced by the order Carnivora during the late Oligocene.

Megistotherium emerged in the Miocene towards the end of the hyaenodonts' flourishing; it was a part of a radiation of African hyaenodontids that occurred at that time.

Hyainailouros sulzeri is very closely related to Megistotherium, extremely similar in size, structure and ratios - with a long tail, short limbs and robust body.

[7] Other authorities[8][9][10] have suggested that Megistotherium is actually a junior synonym of Hyainailouros sulzeri, which is known by an almost complete skeleton, among other remains, and has been found in Europe, Asia and Namibia,[11] and therefore comes from the same localities.

Megistotherium osteothlastes is the only known species from this genus, and it was a large hyainailourid that lived during the Early and Middle Miocene.