(1) Background: Southern Amazonia encompasses some of the most human-impacted and deforested regions of South America, resulting in a hyper-fragmented landscape. In this context, by using a geometric morphometrics approach, we aimed to examine the effect of forest fragmentation on developmental instability (DI) of the mandible, assessed by variation of fluctuating asymmetry (FA), in four neotropical small mammal species inhabiting the municipality of Alta Floresta (Brazil). (2) Methods: The impact of fragment area, fragment shape, isolation, and edge length on DI were assessed by measuring variation in mandibular FA in the long-tailed spiny rat (Proechimys longicaudatus), the hairy-tailed bolo mouse (Necromys lasiurus), the woolly mouse opossum (Marmosa demerarae), and the Amazonian red-sided opossum (Monodelphis glirina). Mandibles from a total of 304 specimens originating from different-sized fragments (ranging from 5 to 900 ha) were used. Twelve homologous landmarks were digitized in photographs of the mesial view of each hemi-mandible. (3) Results: The two largest species, P. longicaudatus and M. demerarae, exhibited significantly higher levels of FA in mandibular shape in small fragments (5-26 ha) in comparison to large ones (189-900 ha). Edge length negatively impacted M. demerarae, the only arboreal species, reinforcing its strongest dependence on core forest habitats. (4) Conclusions: For small mammal communities, we propose that fragments >~200 ha should be the focus of conservation efforts, as both resilient and more sensitive species would benefit from their more preserved biotic and abiotic conditions. Conversely, fragments <~25 ha seem to lead to a significant increase in stress during developmental stages.