Background/Question/Methods Extreme body size reductions can bring about unorthodox anatomical arrangements and novel ways in which animals interact with the environment. Drawing from studies of both vertebrates and invertebrates, we provide a theoretical framework to study miniaturization using lizards as a model system. We illustrate this approach by integrating species’ ecology and evolutionary history. We first identify clades of miniaturized lizards throughout the squamate phylogeny as well as outgroups that are non-miniaturized. Next, we conduct a literature review to extract natural history information for 88 species, including microhabitat and aridity, and perform a meta-analysis to determine whether miniaturized and non-miniaturized lizards differ in ecology. Also, to explore neuroanatomical changes that accompany the evolution of miniaturization, we visualized the brains of one miniaturized and one non-miniaturized gecko species through diceCT scans. Distinctions between the two brain models are enumerated and discussed in the context of sensory ecology and neurophysiological constraints. Through identifying miniaturized lizards in light of body size variation in the phylogeny and exploring ecological and neurophysiological correlates, we offer a starting point in characterizing a syndrome (or suite of traits) associated with miniaturization. Results/Conclusions We demonstrate the repeated evolution of miniaturization across 11 lizard families and high diversity within miniaturized clades, e.g., 101 species within the genus Sphaerodactylus. Through comprehensive assessment of miniaturized lizard species, we argue that lizards are a taxonomic group that offers utility in studies of miniaturization at different phylogenetic scales. Our meta-analysis suggests that miniaturized lizards tend to occupy terrestrial microhabitats, irrespective of biogeographic aridity levels. We hypothesize that this ecological trait may be the outcome of an adaptive shift due to two physiological constraints: evaporative water loss and thermoregulation. Differences in gross brain morphology suggest a disproportionate allocation of neural tissue to regions associated with sensory processing (olfactory tracts and optic tecta) in miniaturized species, though more data are needed to generalize this trend. Scarce ecological data exists for miniaturized lizards and less is known about the intersection of brain morphology, sensory systems, and cognition. Our study brings into light an understudied but potentially influential aspect in vertebrate evolution and gives insights into its effects on ecological and neurophysiological processes. In addition, our findings reveal the need to study the natural history of miniaturized species, which can contribute to a cohesive model of morphological constraints on ecology and neuroanatomy.