The southern Levant experienced losses in mammalian biodiversity since the end of the Pleistocene. This process was more gradual than coeval extinctions in the Americas and Australia. We review data on mammalian communities mainly from Holocene archaeological sites and compare temporal losses and gains of species among size groups of medium-large and small mammals, with markedly differing ecological functions. Species presence vs absence through time within the Mediterranean ecoregion reveals that episodes of local extirpation punctuated the entire Holocene, particularly its later half. The timing of these episodes in the medium-large mammals and the more reduced intensity of such extinctions among small mammals, suggest that likely causes combined direct persecution by human hunters with species-specific vulnerabilities to habitat fragmentation and persistence in anthropogenically modified environments. This distinct south Levantine trajectory is attributed to the complex biogeography of the region, the resulting sensitivity of many local species, which are on the edge of their range of distribution, and long history of pervasive human environmental intervention.