Megistotherium ("greatest beast") is an extinct genus of very large hyaenodont belonging to the family Hyainailouridae that lived in Africa and possibly Asia during the early-middle Miocene epoch, with possible late Miocene records. The first specimen, a near-complete skull, was discovered in 1963 by Robert J. G. Savage in Libya, and was kept at the Natural History Museum in London alongside postcrania discovered in the prior few years. In 1973, Savage described Megistotherium based on these elements, with the skull serving as the type specimen. It was later determined that the assigned postcrania actually came from an amphicyonid, or "bear-dog". One species of Megistotherium, M. osteothlastes, has been described. There is some debate over whether Megistotherium is a genus of its own or a junior synonym of another, related genus, Hyainailouros.

Due to the paucity of material assigned to Megistotherium, size estimates for the genus have varied considerably over the years. The estimate put forward by Savage was 880 kg (1,940 lb). Later efforts have produced estimates ranging from 500–3,002 kg (1,102–6,618 lb), as varying estimates have yielded considerably different results. However, given an apparent upper size limit of 1,100 kg (2,400 lb) for mammalian carnivores due to energetic demands, and the issues with applying size estimates to such fragmentary material, the highest estimates appear unlikely. Regardless, Megistotherium was very large, with a skull measuring 66.4 cm (26.1 in) from front to back, and 47.1 cm (18.5 in) on either side. The number of upper incisors had been reduced to just one, and its upper canines were very large, to such a degree that the front of the snout had expanded outwards to accommodate them. Megistotherium had a very powerful bite force, as evidenced by the size of its zygomatic (cheek) arches and its large sagittal crest. At the same time, it had a very large gape.

Remains assigned to Megistotherium have been discovered in Namibia, Uganda, Kenya, Libya, Egypt, and Pakistan. There is some faunal overlap between some of these localities, such as the Gebel Zelten of Libya and the Moghara of Egypt, and it is likely that Megistotherium would have hunted similar prey across its range. Due to its large body size, strong bite force, and large gape, Megistotherium may have specialised in large prey, such as proboscideans (elephants and their relatives). It has been argued that its extinction may correlate to declines in the populations of these animals, due to the amount of time it takes large mammalian herbivores to breed, as well as competition with the larger-brained and allegedly more social carnivorans. However, this is now considered questionable as studies have found little evidence of brain size and sociality among carnivorans; additionally, cooperative hunting is not widespread in carnivorans, and habitats were unfavorable for pack hunting in Africa during the Early and Middle Miocene.

The Gebel Zelten locality in Libya was first discovered in 1931 by the Italian scientific mission to Kufra. Starting in 1962, a series of geologic expeditions were carried out at the site, with some, such as R. C. Selley's 1963 expedition, being aimed at studying stratigraphy and sedimentology, and others, such as the expeditions of Robert J. G. Savage, being aimed toward the discovery of vertebrate fossils. The first remains of an unknown large predator were discovered in 1962 and 1963 by prospectors. In 1964, during his first expedition, Savage would himself come upon scattered postcranial fragments from such an animal. Only two years later, he discovered the complete skull of a large predatory mammal, specifically a hyaenodont, at a site designated Site 6412, in the southeast corner of the locality. The specimen was catalogued as M.26173 and found its way into the collections of the British Museum of Natural History (now the Natural History Museum, London). In 1973, described both the skull and various other cranial and skull elements, assigning them to a new genus and species of hyaenodont which he named Megistotherium osteothlates; M.26173 was designated as the holotype. Savage believed that several other specimens, such as the very large mandible M.12049 from the Bugti Hills of Pakistan (originally attributed to Anthracotherium), might have belonged to Megistotherium. The postcranial remains assigned to Megistotherium have since been reinterpreted as belonging to an amphicyonid. Remains assigned to Megistotherium have also been described from the Ngorora and Muruyur Formations of Kenya, Egypt, Namibia, and Uganda. A partial right mandible (lower jaw) assigned to the genus, catalogued as DPC 6611 and discovered in strata from the Moghara Formation of Egypt, was described in 1989.

The generic name of Megistotherium comes from Ancient Greek μέγιστον (mégiston) 'greatest' and from Ancient Greek θήριον (thēríon) 'beast'. The species name, osteothlastes, meanwhile, comes from Ancient Greek ὀστέον (ostéon) 'bone' the and from Ancient Greek θλᾰστός (thlastos) 'crushed' or 'bruised' (with -es being an agent noun: 'bone-crusher').

Megistotherium belongs to the subfamily Hyainailourinae, part of the hyainailourid lineage of hyaenodonts. The family Hyainailouridae comprised a diverse group of hyaenodonts that were most successful during the Eocene before being possibly ecologically displaced by the order Carnivora during the late Oligocene. A relationship between M. osteothlastes and Hyainailouros was noted by Savage, who regarded them as "closely allied" with one another. Savage believed that the radiation of large mid-Tertiary hyaenodonts could be encompassed within three genera: Hyainailouros, Megistotherium, and Pterodon.

The cladogram below is based on the results recovered by Matthew R. Borths and Nancy J. Stevens (2019):

The validity of Megistotherium has been questioned by several authors, who suggest that it is actually a junior synonym of Hyainailouros. However, other studies have maintained M. osteothlastes as a separate taxon based on dental characteristics and body size, and others still have done so as a conservative measure; David Tab Rasmussen and colleagues suggested that they may have shared a common ancestor, perhaps a species of Pterodon like P. africanus. The matter is complicated by the paucity of dentition in M. osteothlastes.