Morphological data suggest that Speothos is most closely related to another small canid, Atelocynus (short eared dog).

The skulls of both Speothos and Atelocynus have short nasals that terminate rostral to the maxillary-frontal suture, a character shared with Vulpes (fox genus).

Recent analyses of molecular (mtDNA) data alone and in combination with morphological data support a sister-taxon relationship between Speothos and Chrysocyon (maned wolf); it has been suggested that these highly derived canids diverged at least 3 million years ago, invading South America as separate lineages.

Speothos is distinctive in that it shares similar hypercarnivorous modifications of the dentition with Cuon (dhole) and Lycaon (African wild dog).

The lower carnassial (m1) of Speothos lacks the entoconid, creating a trenchant (cutting) heel on the tooth.