ABSTRACTFacial development requires a complex and coordinated series of cellular events that, when perturbed, can lead to structural birth defects. A quantitative approach to quickly assess morphological changes could address how genetic or environmental inputs lead to differences in facial shape and promote malformations. Here, we report on a method to rapidly analyze craniofacial development in zebrafish embryos using facial analytics based on a coordinate extrapolation system, termed zFACE. Confocal images capture facial structures and morphometric data are quantified based on anatomical landmarks present during development. The quantitative morphometric data can detect phenotypic variation and inform on changes in facial morphology. We applied this approach to show that loss ofsmarca4ain developing zebrafish leads to craniofacial anomalies, microcephaly and alterations in brain morphology. These changes are characteristic of Coffin–Siris syndrome, a rare human genetic disorder associated with mutations inSMARCA4. Multivariate analysis of zFACE data facilitated the classification ofsmarca4amutants based on changes in specific phenotypic characteristics. Together, zFACE provides a way to rapidly and quantitatively assess the impact of genetic alterations on craniofacial development in zebrafish.